Antibody-drug conjugates in clinical trials for lymphoid malignancies and multiple myeloma.

Introduction

Monoclonal antibodies such as rituximab and obinutuzumab are a major component in the combination regimens for the therapy of lymphoid malignancies [ 1 – 6 ]. Antibody-drug conjugates (ADC) are a new class of agents in the treatment of various malignancies. ADC consists of three fundamental elements: a tumor-specific monoclonal antibody (mAb), a cytotoxic small molecule referred to as payload, and a specialized chemical linker that connects the mAb and payload (Fig. 1 ). Upon binding to the corresponding antigen on the surface of tumor cells, the ADC/antigen complex is internalized and then the payloads are released, leading to cytotoxicity and cell death. ADC represents a novel class of anticancer agents that theoretically enhance targeted killing of tumors while sparing normal tissues, thereby maximizing efficacy and minimizing systemic toxicity [ 7 ]. Fig. 1 The schematic diagram of the structure of an antibody-drug conjugate. Antigens for the monoclonal antibody (mAb), linker types, and payloads that are in clinical development were listed

Brentuximab vedotin, inotuzumab ozogamicin, moxetumomab pasudotox, and polatuzumab vedotin are FDA-approved ADCs for lymphoid malignancies [ 8 – 11 ]. More ADCs are under clinical development over the past decade. In this review, we discussed the general principles of ADC design and updated on novel ADCs in clinical trials for the treatment of lymphoid malignancies and multiple myeloma.

Engineering ADCs

Selection of antigens and antibodies

An ideal antigen for targeted therapy should have a high copy number on tumor cells with limited or no expression in normal tissues to minimize off-target ADC uptake [ 12 ]. The antigen should be able to trigger intracellular internalization upon ADC binding. When an antigen target has heterogenous expression, optimal antitumor activity relies more on the bystander effect, which is referred to as the ADC’s ability to diffuse across cell membranes and exert cytotoxicity on the neighboring cells. This bystander effect is frequently influenced by the chemical nature of the payloads and linkers of the ADCs [ 13 , 14 ].

Immunoglobulin G (IgG) is the most frequently used subtype in ADCs due to the longer half-life, and the most chosen isotype is IgG1 [ 15 ]. IgG1 can induce stronger antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which further enhance the antitumor effect of ADCs [ 16 ]. However, the ADCC and CDC activities intrinsic to the antibodies may add additional toxicities to the cytotoxic payloads. One solution is to engineer the Fc portion of IgG1 heavy chain by introducing mutations to silent the intrinsic effector immune function [ 17 ]. IgG2 is believed to conjugate more payloads because it contains four reducible interchain disulfide bonds, whereas IgG1 and IgG4 have only two such bonds [ 18 ]. IgG4 has the tendency to exchange with other antibodies, therefore IgG4-based ADCs, such as inotuzumab ozogamicin, often contain a stabilizing mutation in the hinge region to prevent half antibody exchange [ 19 ].

Characteristics of payloads

The payloads used in ADCs are selected small molecules with high potency and proper hydropholicity [ 20 , 21 ]. Another important parameter is drug-antibody ratio (DAR), which is defined as the average number of payload molecules attached to a single mAb. The ideal level of DAR is between 3 and 4. The DAR affects the drug stability in the circulation, tumor penetration capability, antitumor efficacy, and toxicity of an ADC [ 22 ].

The payloads commonly used in ADCs can be divided into two main categories: microtubule inhibitors and DNA-damaging agents. Two currently employed microtubule inhibitors are maytansinoids and auristatins. Maytansinoids were initially derived from maytansine, a natural benzoansamacrolide discovered in the plant maytenus ovatus [ 23 ]. There are two maytansinoids derivatives: DM1 and DM4. DM1 includes emtansine and mertansine. DM4 includes soravtansine and ravtansine. Auristatins are extracted from the sea hare Dolabella auricularia . Two auristatin derivatives are commonly used for ADC constructions: monomethyl auristatin E (MMAE, vedotin) and monomethyl auristatin F (MMAF, mafodotin) [ 24 – 31 ]. MMAE is toxic to the neighboring cells through the bystander effect due to its neutral charge that allows diffusion across cell membranes. MMAE has been used in brentuximab vedotin and polatuzumab vedotin. MMAF lacks the ability of bystander killing [ 32 ]. DNA-damaging agents include calicheamicin, pyrrolobenzodiazepines (PBD) dimer, indolinobenzodiazepines, duocarmycins, doxorubicin, etc. [ 33 ]. Calicheamicin has been used in inotuzumab ozogamicin and gemtuzumab ozogamycin [ 11 , 34 – 36 ].

Linker selections and conjugation strategies

An ideal linker should not allow premature deconjugation in the circulation which triggers off-target toxicity. Linkers currently used in ADCs fall into two broad categories: cleavable and non-cleavable linkers. Cleavable linkers are sensitive to several intracellular conditions. Here are some examples. Hydrazone, an acid-labile linker used in inotuzumab ozogamicin, can be selectively hydrolyzed in the acidic pH environment inside the lysosomes and endosomes. However, slow hydrolysis under physiologic condition in circulation has been reported [ 37 ]. Protease-cleavable linkers contain dipeptide sequences like valine-citrulline (Val-Cit) and valine-alanine (Val-Ala) that can be recognized by cathepsin B. These linkers are often coupled with p -aminobenzyloxycarbonyl (PABC) which serves as a spacer between the dipeptide and payload. Protease cleavable linkers show relatively higher stability in plasma. Val-Cit linker has been used to construct brentuximab vedotin [ 38 ]. Typical disulfide linkers include N -succinimidyl-4-(2-pyridylthio) butanoate (SPDB) and N -succinimidyl-4-(2-pyridyldithio) pentanoate (SPP) [ 39 ].

Non-cleavable linkers are more stable but rely on complete proteolytic degradation of the whole mAb backbone by the lysosomes to release active payloads. Most common examples of non-cleavable linkers are thioether linkers, N -succinimidyl-4-( N -maleimidomethyl)cyclohexane-1-carboxylate SMCC) and maleimidocaproyl (MC) [ 40 ].

Multiple conjugation strategies have been developed to attach linkers to a specific amino acid residue on the mAb. Lysine is one of the most common amino acid residues used to connect linkers with activated carboxylic acid esters [ 41 ]. Cysteine-based conjugation has been used in brentuximab vedotin and a variety of ADCs under development. It has been further improved by a new engineered cysteine technology, THIOMAB, that generates highly homogeneous ADCs with a controlled DAR of 2 [ 42 ].

Homogeneous ADCs can also be achieved through site-specific conjugation by incorporating genetically engineered non-natural amino acid (nnAA) [ 43 , 44 ]. Other conjugation methods include enzymatic conjugations such as transpeptidation mediated by sortase or bacterial transglutaminases, N -glycan engineering by β-1,4-galactosyltransferase and α-2,6-sialyltransferase, etc. [ 45 – 47 ].

ADCs approved for lymphoid malignancies

Brentuximab vedotin (Adcetris®, SGN-35)

Brentuximab (BV) is composed of an anti-CD30 chimeric IgG1 mAb conjugated to MMAE via a protease-cleavable linker [ 48 ]. CD30 is a tumor necrosis factor (TNF) receptor superfamily member, characteristically expressed on the surface of Reed–Sternberg cells in Hodgkin lymphoma (HL) [ 49 ], anaplastic large cell lymphoma (ALCL) cells, and a subset of cutaneous T cell lymphoma (CTCL) cells, with limited expression on normal cells [ 50 ].

Single-agent BV has been approved by the US FDA in 2011 for the treatment of HL after failure of autologous stem cell transplantation (ASCT) or after failure of at least two prior multiagent chemotherapy regimens [ 8 , 49 , 51 , 52 ] (Table 1 ). In a pivotal phase II trial ( NCT00848926 ), 102 patients with relapsed/refractory (R/R) HL who failed ASCT were treated with intravenous BV 1.8 mg/kg every 3 weeks at a maximum of 16 cycles in the absence of disease progression or unacceptable toxicity. The overall response rate (ORR) was 75% with 34% complete remission (CR) and the median duration of response (DOR) was 6.7 months. The most common treatment-emerging adverse events (TEAE) were peripheral sensory neuropathy (42%), nausea (35%), fatigue (34%), and neutropenia (19%). Fifty-five percent of patients experienced grade ≥ 3 AEs (SAE), majority of which included neutropenia (20%) and peripheral sensory neuropathy (8%). Most of these AEs are manageable with dose reductions and/or delays [ 8 , 53 ]. At the 5-year follow-up, the overall survival (OS) and progression-free survival (PFS) rate for all patients were 41% and 22% respectively. The estimated median OS and PFS were 40.5 and 9.3 months respectively, suggesting long-term disease control provided by single-agent BV [ 54 ]. However, many patients still eventually developed resistance partially because of the upregulation of multidrug resistance pump (MDR1), a drug export pump. Currently, a phase I trial ( NCT03013933 ) is investigating the combination of BV and cyclosporine (CsA), an MDR1 inhibitor, for R/R HL. The interim result was encouraging, showing a 67% ORR (33 % CR) and a manageable toxicity profile at the maximum tolerated dose (MTD) [ 55 ]. Table 1 FDA approved antibody-drug conjugates for B cell malignancies and multiple myeloma ADC names Target Indications Dosage and schedule Year of approval Brentuximab vedotin (Adcetrix®) CD30 R/R HL - 1.8 mg/kg (maximum 180 mg) - Every 3 weeks until disease progression or unacceptable toxicity 2011 Frontline stage III & IV HL (+ AVD) - 1.2 mg/kg (maximum 120 mg) combined with chemotherapy - Every 2 weeks until a maximum of 12 doses, disease progression, or unacceptable toxicity 2018 Post-ASCT consolidation for HL - 1.8 mg/kg (maximum 180 mg) - Initiate within 4–6 weeks post-ASCT or upon recovery from ASCT - Every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity 2015 R/R systemic ALCL - 1.8 mg/kg (maximum 180 mg) - Every 3 weeks until disease progression or unacceptable toxicity 2011 R/R PTCL (+ CHP) - 1.8 mg/kg (maximum 180 mg) combined with chemotherapy - Every 3 weeks with each cycle of chemotherapy for 6 to 8 doses 2018 R/R CTCL - 1.8 mg/kg (maximum 180 mg) - Every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity 2017 Inotuzumab ozogamicin (Besponsa®) CD22 R/R B-cell ALL - Cycle 1 (21 day-cycle): 1.8 mg/m 2 [day 1 (0.8 mg/m 2 ), day 8 (0.5 mg/m 2 ), and day 15 (0.5 mg/m 2 )] - Subsequent cycles (28 day-cycle): 1) Patients who have achieved CR or CRi: 1.5 mg/m 2 [day 1 (0.5 mg/m 2 ), day 8 (0.5 mg/m 2 ), and day 15 (0.5 mg/m 2 )] per cycle 2) Patients who have not achieved CR or CRi: repeat cycle 1 - Duration: 1) Patients proceeding to ASCT: 2 cycles 2) Patients not proceeding to ASCT: maximum 6 cycles 2017 Moxetumomab pasudotox (Lumoxiti®) CD22 R/R HCL - 0.04 mg/kg on days 1, 3, and 5 of each 28-day cycle. - Maximum of 6 cycles, disease progression, or unacceptable toxicity 2018 Polatuzumab vedotin (Polivy®) CD79b R/R DLBCL (+ BR) - 1.8 mg/kg per cycle, combined with BR - every 21 days for 6 cycles 2019 ALCL anaplastic large cell lymphoma, ALL acute lymphoblastic leukemia, ASCT autologous stem cell transplant, BR bendamustine and rituximab, CR complete remission, CTCL cutaneous T cell lymphoma, DLBCL diffuse large cell lymphoma, HCL hairy cell leukemia, HL Hodgkin lymphoma, NHL non-Hodgkin lymphoma, PTCL peripheral T cell lymphoma, R / R relapsed/refractory

BV plus bendamustine (BVB) has been studied as a salvage regimen for R/R HL with favorable toxicity profile in phase I/II trials. One study ( NCT01657331 ) revealed that BVB achieved a 78% ORR in heavily pretreated HL patients. Grade 3 to 4 neutropenia were found in 25% of patients across the trial [ 56 ]. Another study ( NCT01874054 ) used BVB as the first salvage regimen for 55 HL patients who failed the frontline therapy. A better outcome was reported with a 92.5% ORR (73.6% CR) and a 62.6% estimated 2-year PFS. Further, 75.4% patients proceeded to ASCT. Most frequently reported SAEs included rash (16.3%), lymphopenia (10.9%), and hypotension (7.3%) [ 57 ]. There is another ongoing trial ( NCT01657331 ) that identified 23 out of 65 patients treated with BVB who experienced prolonged median PFS of more than 1 year [ 58 ]. BV in combination with nivolumab (Nivo) represents another ongoing clinical trial for R/R HL. In the phase I/II trial ( NCT02572167 ), BV + Nivo achieved 82% ORR and 61% CR, almost doubled the CR rate of BV monotherapy in the pivotal phase II trial. There were mostly grade 1 and 2 AEs: nausea (49%), fatigue (41%), infusion-related reactions (44%) [ 59 ]. Currently, BVB and BV + Nivo are being compared in an ongoing phase II trial ( NCT02927769 ).

BV is an effective option of consolidation therapy both before and after ASCT for HL at a high risk of relapse or progression. A randomized, double-blind, multinational, phase III trial (AETHERA, NCT01100502 ) enrolled 329 eligible patients to receive either 16 cycles of 1.8 mg/kg intravenous BV or placebo every 3 weeks, starting 30–45 days after transplantation. Median PFS was 42.9 months for patients in the BV group ( n = 165), significantly better than the 24.1 months in the placebo group ( n = 164) [ 60 ]. There was continued benefit at 5-year follow-up, with PFS rate for patients receiving BV and placebo at 59% and 41% respectively [ 61 ]. The toxicity profile mainly consisted of peripheral neuropathy (56%) and neutropenia (35%), with neutropenia (29%) being the most common SAE [ 60 ]. Recently, a retrospective multicenter study revealed that chemo-refractory HL patients receiving BV prior to allogeneic SCT (AlloSCT) presented with a better outcome and a lower incidence of chronic graft versus host disease (GVHD) at 3-year follow-up compared to those without BV (PFS 53% vs. 33%; OS 62% vs. 44%; GVHD incidence 43% vs. 47%) [ 62 ].

BV in combination with chemotherapy has been reported to optimize the frontline treatment of newly diagnosed advanced stage HL. This report was from the international randomized phase III trial (ECHELON-1, NCT01712490 ) which assigned patients with previously untreated stage III or IV classic HL to receive either BV (adcetris) plus doxorubicin, vinblastine, and dacarbazine (AAVD) ( n = 664) or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) ( n = 670) [ 51 ]. The outcome of the AAVD cohort appeared to be superior to the ABVD cohort in terms of the 2-year modified PFS (81.0% vs. 74.4%), which was further confirmed by sensitivity analysis, even though the response rate was not significantly different between the two cohorts: ORR (86% vs. 83%), CR (73% vs. 70%). Of note, patients receiving AAVD presented with a higher incidence of peripheral neuropathy (29% vs. 17%) but a lower incidence of pulmonary toxicity (< 1% vs. 3%) than patients receiving ABVD. Neutropenia (54% vs. 39%) was the most frequently encountered SAE in both cohorts. Prophylaxis with granulocyte colony-stimulating factor (G-CSF) effectively decreased the rate of neutropenia and febrile neutropenia [ 51 , 63 ].

BV plus etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), a modified first-line treatment for advanced classical HL by incorporating BV was reported with an 88% CR rate and a more favorable toxicity profile ( NCT01569204 ) [ 64 ]. This BrECADD regimen is currently being compared to the standard BEACOPP chemotherapy in a phase III randomized trial (HD21, NCT02661503 ).

BV has been studied in a few subtypes of non-Hodgkin lymphoma (NHL), including systemic ALCL, an aggressive CD30 + subtype of peripheral T cell lymphoma (PTCL). In a phase II multicenter trial ( NCT00866047 ), 58 patients with systemic ALCL after failure of at least one prior multiagent chemotherapy regimen received intravenous BV 1.8 mg/kg every 3 weeks. Fifty (86%) patients achieved ORR, and 33 (57%) achieved CR [ 65 ]. For all enrolled patients, the estimated 5-year OS and PFS were 60% and 39% respectively. Among those who achieved CR, the 5-year OS and PFS were 79% and 57% respectively. Of the 50 patients with an objective response, the median duration of response (DOR) was 25.6 months [ 66 ]. In 2018, FDA approved BV in combination with cyclophosphamide, doxorubicin, and prednisone (CHAP) for the treatment of CD30-expressing PTCL including systemic ALCL, angioimmunoblastic T cell lymphoma, and PTCL not otherwise specified, based on the positive result of a randomized, double-blind phase III trial (ECHELON-2, NCT01777152 ). In this study, 452 PTCL patients were randomized to receive either CHAP or cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The patients in the CHAP group had longer PFS (48.2 months vs. 20.8 months), a higher ORR (83% vs. 72%), and CR rate (68% vs. 56%). Most common AEs of CHAP recipients were nausea (46%), peripheral neuropathy (45%), neutropenia (38%), and diarrhea (38%), comparable to those of CHOP recipients. Neutropenia (35%) was the most common SAE [ 67 ]. BV has also been investigated in cutaneous T cell lymphoma (CTCL). In a multicenter randomized phase III trial (ALCANZA, NCT01578499 ) that enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous ALCL who had received prior systemic therapy, patients receiving BV demonstrated more favorable outcome than those receiving conventional therapy (methotrexate or bexarotene): ORR lasting at least 4 months (56.3% vs. 12.5%), CR (16% vs 2%), and median PFS (17.2 vs. 3.5 months). A higher level of CD30 expression seemed to be associated with a better response to treatment with BV. There were mostly grade 1 to 2 AEs in BV-treated patients. Of note, the incidence of reported peripheral neuropathy (45%; grade ≥ 3: 5%) was much higher than that in patients receiving conventional therapy. Other common AEs included nausea (36%), diarrhea (29%), and fatigue (29%) [ 68 ].

In addition, several studies suggested that BV could provide additional treatment options for patients suffering from R/R B-cell NHL [ 69 , 70 ]. In one phase II trial ( NCT01421667 ) that enrolled 49 patients with heavily pretreated diffuse large B cell lymphoma (DLBCL), there was a 44% ORR with a 17% CR, and the DOR was 16.6 months [ 69 ].

Inotuzumab ozogamicin (Besponsa®, CMC-544)

Inotuzumab ozogamicin (InO) is composed of a humanized anti-CD22 IgG4 mAb conjugated to calicheamicin via an acid-labile linker [ 71 ]. CD22 is a B cell-restricted transmembrane sialoglycoprotein, present on the surface of mature B cells, and thought to be involved in signal transduction, B cell activation and regulation [ 11 , 71 ]. CD22 is also expressed by most B cell malignancies, including leukemic blasts in > 90% patients with B cell ALL, as well as chronic lymphocytic leukemia (CLL), NHL, and hairy cell leukemia (HCL) [ 72 , 73 ]. Therefore, CD22 represents an important therapeutic target for ALL and other B cell malignancies.

InO has been approved by the US FDA in 2017 for the treatment of R/R CD22-positive B cell ALL [ 9 , 10 ]. The approval was mainly based on a phase III, international, randomized trial (INO-VATE, NCT01564784 ) designed to compare single-agent InO with chemotherapy regimens as first or second salvage therapy for R/R ALL patients. Three hundred thwenty-six adult patients were randomized to receive either InO ( n = 164) or standard of care (SoC, intensive chemotherapy; n = 162) [ 74 ]. The CR/CR with incomplete hematologic recovery (CRi) rate was significantly higher in patients in the InO arm (73.8%) compared to those in the SoC arm (30.9%). Both PFS and OS were longer with InO than SoC: the median PFS was 5.0 vs. 1.7 months, the median OS was 7.7 vs. 6.2 months, and the 2-year OS rate was 22.8% vs. 10.0%. Subset analyses revealed that remission rates remained consistent for patients with Philadelphia chromosome-positive (Ph+) or -negative (Ph−) ALL. Interestingly, more patients in the InO arm proceeded directly to AlloSCT after achieving CR/CRi (39.6% vs. 10.5%), suggesting InO as an effective bridging therapy to transplantation [ 75 ]. Besides, InO-treated patients reported a better quality of life than those receiving SoC [ 76 ]. Frequent AEs reported by InO recipients were neutropenia (36%), thrombocytopenia (29%), anemia (18%), febrile neutropenia (16%), nausea (15%), and pyrexia (11%), with lower incidences than SoC recipients [ 74 ]. However, there is a higher incidence of hepatotoxicity especially veno-occlusive disease (VOD) (14% vs. 2.1%), which is also the most common SAE found in InO recipients. Of note, among patients who proceeded to AlloSCT, 22% of InO recipients developed VOD after transplantation compared to only 3% of SoC recipients [ 77 ]. In view of this risk, expert opinions recommended that for patients planning to receive AlloSCT, InO administration should be limited to two cycles. Transplantation conditioning regimens containing two alkylating agents or any concomitant hepatotoxic drugs should be avoided [ 78 ]. Besides, patients receiving InO should also be monitored for prolonged QTc and tumor lysis syndrome. Interestingly, weekly low doses of InO has been revealed to result in less AEs than single-dose InO [ 79 ]. Currently, there is an ongoing trial evaluating the efficacy of weekly low-dose InO for R/R CD22-positive ALL ( NCT03094611 ).

In addition to monotherapy, InO has been studied in combination with chemotherapy for R/R B cell ALL. InO was added to the treatment cycles of mini-hyper-CVD (miniHCVD), which was a modified hyper-CVAD regimen (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with no anthracycline, whereas cyclophosphamide and dexamethasone were given at 50% dose reduction, methotrexate at 75% dose reduction, and cytarabine at 0.5 mg/m 2 for four doses [ 80 ]. InO was added on day 3 of each cycle with 1.3 mg/m 2 in cycle 1 and 1 mg/m 2 in subsequent cycles. A phase II trial ( NCT01371630 ) enrolled 59 patients with R/R B cell ALL receiving InO-miniHCVD. The regimen showed a 78% ORR (59% CR) and a minimal residual disease (MRD) negativity of 82% among responders. The median OS and PFS were 11 and 8 months respectively, and the 1-year overall OS and PFS rates were 46% and 40% respectively. Subset analysis showed that the OS rate was much higher in patients who were treated in first salvage than those in subsequent salvages. Notably, 44% patients proceeded to subsequent ASCT suggesting InO + miniHCVD as an option for bridging therapy. The most common SAEs reported were thrombocytopenia (81%) and infections (73%). VOD still occurred in 15% of patients [ 81 ]. Even though InO + miniHCVD seemed to present with more favorable outcomes compared to the INO-VATE trial, further phase III studies are still warranted to ascertain the value of this combination therapy.

InO-miniHCVD has also been investigated as a frontline therapy in older patients (≥ 60 years) with newly diagnosed Ph− B cell ALL [ 82 ]. A single-arm phase II trial ( NCT01371630 ) conducted in MD Anderson Cancer Center first reported that InO-miniHCVD demonstrated robust activity (ORR 98%, CR 85%, 3-year OS 56%, and 3-year PFS 49%). Frequently reported SAEs were thrombocytopenia (81%), infections occurred during induction (52%) or consolidation (69%), hyperglycemia (54%), and hepatic events including VOD (33%) [ 82 ]. In an attempt to further reduce toxicity and length of maintenance, blinatumomab (blina), a bispecific T cell-engaging antibody targeting both CD19 and CD3 [ 83 – 86 ], was added to the regimen. This new regimen, InO-miniHCVD with or without blina, achieved a 98% ORR (87% CR) and a 54% 3-year OS according to the interim result of an ongoing phase II trial ( NCT03249870 ), comparable to the previous one [ 87 ]. A recently published retrospective propensity score analysis reported that older patients with newly diagnosed Ph− ALL who received InO-miniHCVD ± blina demonstrated better outcomes and lower risks than those who received hyper-CVAD (ORR 98% vs. 88%; 3-year OS 64% vs. 34%; early death 0% vs. 8%) [ 88 ]. Currently, there is another ongoing trial examining combination of InO with hyper-CVAD as a frontline therapy for ALL patients ( NCT03488225 ).

The development of InO in B cell lymphoma has made relatively less progress. Single-agent InO was administered to 81 patients with R/R B cell NHL, predominantly follicular lymphoma (FL), who failed rituximab, rituximab plus chemotherapy, or radioimmunotherapy in a phase II trial ( NCT00868608 ). The study reported a 67% ORR, a 31% CR, and a median PFS of 12.7 months. Bone marrow suppression was reported with most frequently thrombocytopenia (74%) and neutropenia (56%). Of note, 58% of patients with AEs discontinued the treatment [ 89 ]. InO combined with rituximab (R-InO) is thought to be a treatment option for patients with R/R B cell NHL who are not candidates for high-dose chemotherapy. One phase I/II trial ( NCT00299494 ) reported that the R-InO regimen at MTD (1.8 mg/m 2 InO plus 375 mg/m 2 rituximab) yielded an 87% ORR for R/R FL and 74% ORR for R/R DLBCL. R-InO demonstrated a similar toxicity profile to the single-agent InO [ 90 ]. A separate phase II trial ( NCT00867087 ) reported only 29% ORR after 3 cycles of R-InO for patients with R/R DLBCL [ 91 ]. However, a recent randomized phase III trial ( NCT01232556 ) revealed that the outcome of the R-InO recipients appeared not to be superior to those receiving rituximab plus chemotherapy of bendamustine or gemcitabine in terms of ORR (41% vs. 44%), OS (35% vs. 37%), and PFS (19% vs. 17%) [ 92 ]. Several clinical trials are exploring different new regimens. InO at 0.8 mg/m 2 combined with full dose of rituximab, cyclophosphamide, vincristine, and prednisolone (R-CVP) was reported safe and effective for CD22 + R/R B cell NHL in a phase I trial ( NCT01055496 ). The ORR was 84% with 24% CR. Subset analysis showed that ORR was 100% for patients with indolent lymphoma and 57% for those with aggressive histology. The toxicity profile was also similar to InO monotherapy [ 93 ]. Currently, InO + R-CVP is being evaluated in patients with DLBCL not suitable for anthracycline-based chemotherapy in a phase II trial ( NCT01679119 ). InO at 0.8 mg/m 2 plus full dose rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) is a regimen proposed by another phase I trial ( NCT01055496 ) for patients with R/R CD22 + B cell NHL. The preliminary result was less encouraging (53% ORR; 20% CR) [ 94 ].

Moxetumomab pasudotox (Lumoxiti®, CAT-8015)

Moxetumomab pasudotox (MP) is the second anti-CD22 ADC that comes into clinical practice. It has the Fv fragment of a recombinant murine mAb with higher affinity for CD22 than the parent compound [ 95 ]. The fragment is genetically fused to a truncated form of Pseudomonas aeruginosa exotoxin (PE38) [ 96 ]. MP has been approved by the US FDA in September 2018 for the treatment of adult patients with R/R hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including two courses of a purine analog or one course of rituximab or a BRAF inhibitor following a single course of a purine analog. The approval was mainly based on a pivotal, multicenter, open-label, single-arm trial ( NCT01829711 ) that enrolled 80 patients who received 40 μg/kg MP intravenously on days 1, 3, and 5 every 28 days for a maximum of 6 cycles. The treatment led to a 75% ORR with 41% CR. Eighty-five percent of CR patients achieved MRD negativity. PFS was not yet reached at a median follow-up of 16.7 months. The median DOR for the MRD-positive patients was 5.9 months and has not been reached for MRD-negative patients [ 97 ]. Elimination of MRD has been shown to be associated with prolonged CR duration [ 98 ]. The most common treatment-emerging AEs (TEAE) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Serious AEs included hemolytic uremic syndrome (HUS) (8%) and capillary leak syndrome (CLS) (5%). Although four of HUS and two of CLS patients ended up with discontinuation of therapy, most of the above AEs were manageable with dose reduction and supportive care [ 97 , 99 ]. It was noted that antidrug titers increased after repeated administration of the ADC [ 99 ]. Currently, a phase I trial ( NCT03805932 ) is looking at whether the combination of MP and rituximab is safe and effective for R/R HCL. The development of MP for precursor cell lymphoblastic leukemia/lymphoma, NHL, and CLL has been discontinued [ 99 ].

Polatuzumab vedotin (Polivy®, DCDTS4501A)

CD79b is a component of the B cell receptor (BCR) complex [ 100 ]. It is a promising therapeutic target because of its restricted expression on mature B cells and B cell malignancies [ 101 ]. Polatuzumab vedotin (Pola) is an anti-CD79b mAb conjugated to MMAE via a protease-cleavable linker similar to the structure of anti-CD22 ADC, pinatuzumab vedotin (Pina). Phase I trials demonstrated that single-agent Pola at a recommended dose of 2.4 mg/kg was effective against NHL but not for CLL [ 102 ]. Both pola and pina were often studied in combination with rituximab. The ROMULUS trial showed that irrespective of CD79b expression, R-Pola was associated with a 54% ORR (21% CR), and a median PFS of 5.6 months for DLBCL patients, which was comparable to those from R-Pina; but for FL patients, R-Pola was associated with a 70% ORR (45% CR), and a median PFS of 15.3 months, much more effective than R-Pina. R-Pola shared a similar profile of AEs with R-Pina, but less incidence of SAEs [ 103 ]. Therefore, the overall risk-benefit ratio favored Pola for further investigation in B cell NHL.

In an ongoing randomized phase II trial ( NCT02257567 ), Pola was added to the regimen of bendamustine plus rituximab (BR) or obinutuzumab (BO) for patients with R/R DLBCL or R/R FL ineligible for autologous stem cell transplantation (ASCT). The interim result showed that the addition of Pola significantly improve ORR (45% vs. 18%), CR (40% vs. 18%), median OS (12.4 vs. 4.7 months), and PFS (7.6 vs. 2.0 months) [ 104 ]. For the R/R DLBCL patients in this randomized phase II trial, 40 patients received Pola-BR, and 40 patients were randomized to BR only arm. In the Pola-BR arm, 25 (63%) patients achieved a PR/CR, versus 25% in the BR arm. The DOR was also longer in the pola-BR arm. Pola has been approved by FDA in June 2019 for R/R DLBCL who have failed at least two prior therapy and are not eligible for ASCT (Table 1 ). Pola is infused at 1.8 mg/kg over 90 min in combination with BR for the first cycle. Subsequent infusions may be administered over 30 min if the previous infusion is tolerated. The Pola-BR regimen is given every 21 days for a total of 6 cycles. One phase I/II trial ( NCT01992653 ) reported that Pola plus obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (Pola-G-CHP) yielded a 91% ORR (81% CR) with manageable toxicity profile. Common SAEs were neutropenia (38%) and febrile neutropenia (33%) [ 105 ]. Another phase I/II trial ( NCT01992653 ) investigated the combination of Pola with rituximab-cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP). An encouraging response with 91% ORR (78% CR) was also achieved. Most common SAEs were neutropenia (27%) and febrile neutropenia (11%) [ 106 ]. A multicenter, randomized, double-blind, placebo-controlled phase III trial (POLARIX, NCT03274492 ) is currently ongoing to compare Pola-R-CHP to rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as the first-line treatment for patients with newly diagnosed DLBCL.

ADCs under clinical development for lymphoid malignancies

Anti-CD19 ADCs

CD19 is a transmembrane glycoprotein that is essential in modulating both B cell receptor-dependent and independent signaling. It is ubiquitously expressed in the B lymphocyte lineage, from the earliest B lineage committed cells, and continuing through pre-B and mature B cell stage. CD19 is present in the majority of B cell malignancies. CD19 is therefore a genuine biomarker for normal and malignant B cells, making it an ideal therapeutic target [ 107 ].

Coltuximab ravtansine (SAR3419) is a humanized anti-CD19 IgG1 mAb conjugated to DM4 via a cleavable disulfide linker [ 108 ] (Table 2 ). In a phase II trial ( NCT01472887 ), SAR3419 was administered to patients with R/R DLBCL previously treated with rituximab-containing regimen. The dose used in this study was 55 mg/m 2 weekly for 4 weeks, then every 2 weeks for the next four doses. The study achieved a 43.9% ORR (14.6% CR), and a median OS and PFS of 9.2 and 4.4 months respectively. In contrast to limited efficacy, the safety profile was favorable. Common AEs were mainly gastrointestinal disorders such as diarrhea and nausea (43%), asthenia (30%), and ocular toxicity (25%). Most common SAEs were hepatotoxicity (3%) and abdominal pain (3%) [ 109 ]. Another phase II trial combined SAR3419 with rituximab for R/R DLBCL, but the trial resulted in a less favorable clinical response compared to the previous single-agent trial [ 119 ]. SAR3419 has also been evaluated in patients with R/R ALL in a phase II trial ( NCT01440179 ), but ORR was only 25.5%. This trial was terminated [ 120 ]. Table 2 Antibody-drug conjugates in clinical trials for lymphoid malignancies ADC names Target Linker Payload Indications Major responses Status [reference] Brentuximab vedotin (Adcetrix®) CD30 Protease-cleavable (Val-Cit) MMAE R/R HL ORR 75%, CR 34%; OS 40.5 months, PFS 9.3 months; 5-year OS 41%, PFS 22%; Approved [ 54 ] Frontline stage III & IV HL (+ AVD) ORR 86%, CR 73%, 2-year PFS 81% Approved [ 51 ] Post-ASCT consolidation for HL PFS 42.9 months, 5-year PFS 59% Approved [ 60 , 61 ] R/R systemic ALCL ORR 86%, CR 57%, 5-year OS 79%, PFS 57%, DOR 25.6 months Approved [ 65 , 66 ] R/R PTCL (+ CHP) ORR 83%, CR 68%, PFS 48.2 months Approved [ 67 ] R/R CTCL ORR 56.3%, CR 16%, PFS 17.2 months Approved [ 68 ] Inotuzumab ozogamicin (Besponsa®) CD22 Acid-labile (hydrazone) Calicheamicin R/R B-cell ALL, CR/CRi 73.8%, OS 7.7 mo, PFS 5 months Approved [ 74 , 75 ] Frontline Ph- B-cell ALL (+ miniHCVD) ORR 98%, CR 85%, 3-year OS 56%, PFS 49% Phase II [ 82 ] R/R B-cell NHL ORR 67%, CR 31%, PFS 12.7 months Phase II [ 89 ] Moxetumomab pasudotox (Lumoxiti®) CD22 Disulfide bond PE38 R/R HCL ORR 75%, CR 41%, PFS not reached at 16.7-month follow up Approved [ 97 , 98 ] Polatuzumab vedotin (DCDTS4501A) CD79b Protease-cleavable (Val-Cit) MMAE R/R DLBCL (+ BR) ORR 63%, PFS 7.6 months, OS 12.4 months Approved [ 103 ] Newly diagnosed DLBCL (+ G-CHP or + R-CHP) G-CHP: ORR 91%, CR 81%; R-CHP: ORR 91%, CR 78%; Phase III [ 105 , 106 ] Coltuximab ravtansine (SAR3419) CD19 Disulfide bond (SPDB) DM4 R/R DLBCL ORR 43.9%, CR 14.6%, OS 9.2 months, PFS 4.4 months Phase II [ 109 ] Denintuzumab mafodotin (SGN-CD19A) CD19 Non-cleavable (MC) MMAF R/R B-cell ALL ORR 35%, CR 19%, DOR 27 weeks Phase I [ 110 ] R/R DLBCL ORR 33%, CR 22%, DOR 40 weeks Phase I [ 111 ] Loncastuximab Tesirine (ADCT-402) CD19 Protease-cleavable (Val-Ala) PBD dimer R/R B-cell ALL CR 8.7% Phase I [ 112 ] R/R NHL DLBCL: ORR 40.2%, CR 22% MCL: ORR 46.7%, CR 26.7%; FL: ORR 80%, CR 53.3% Phase I [ 113 , 114 ] Pinatuzumb vedotin (DCDT2980S) CD22 Protease-cleavable (Val-Cit) MMAE R/R B-cell NHL (+ Rituximab) DLBCL: ORR 60%, CR 26%, PFS 5.4 months; FL: ORR 62%, CR 5%, PFS 12.7 months Phase II [ 103 ] Camidanlumab tesirine (ADCT-301) CD25 Protease-cleavable (Val-Ala) PBD dimer R/R HL ORR 80.8%, CR 50%, DOR 7.7 months, PFS 6.7 months Phase I [ 115 ] R/R B and T cell NHL B: ORR 31.3%, CR 18.8%; T: ORR 50%, CR 0 Phase I [ 116 ] Naratuximab emtansine (IMGN529) CD37 Non-cleavable (SMCC) DM1 R/R B-cell NHL ORR 13%, CR 2.6% Phase I [ 117 ] AGS67E CD37 Protease-cleavable (Val-Cit) MMAE R/R B and T cell NHL ORR 22%, CR 14% Phase I [ 118 ] ADC antibody-drug conjugate, ALCL anaplastic large cell lymphoma, ALL acute lymphoblastic leukemia, CTCL cutaneous T cell lymphoma, HL Hodgkin lymphoma, NHL non-Hodgkin lymphoma, R / R relapsed/refractory, MM multiple myeloma, CR complete remission, DLBCL diffuse large cell lymphoma, DOR duration of response, FL follicular lymphoma, MCL mantle cell lymphoma, ORR overall response rate, OS overall survival, PFS progression-free survival, PTCL peripheral T cell lymphoma

Denintuzumab mafodotin (SGN-CD19A) is a humanized anti-CD19 IgG1 mAb conjugated to MMAF via a non-cleavable MC linker. A phase I trial ( NCT01786096 ) of SGN-CD19A showed a 35% ORR (19% CR) and a median DOR of 27 weeks in patients with R/R B cell ALL. Most frequently reported AEs were pyrexia (54%), nausea (52%), fatigue (51%), headache (44%), chills (38%), vomiting (37%), and blurry vision (35%) [ 110 ]. A separate phase I trial ( NCT01786135 ) in patients with R/R DLBCL revealed a 33% ORR (22% CR) and a median DOR of 40 weeks. Of note, ocular toxicity, such as blurry vision (65%), dry eye (52%), and keratopathy (35%), was prominent [ 111 ]. Two phase II trials were evaluating the combination of SGN-CD19A and other regimens ( NCT02855359 : R-CHP or R-CHOP; NCT02592876 : RICE [rituximab, ifosfamide, carboplatin, and etoposide]) in DLBCL, but were currently on hold.

Loncastuximab tesirine (ADCT-402) is a humanized anti-CD19 IgG1 mAb conjugated through a protease-cleavable Val-Ala linker to a PDB dimer, a DNA crosslinking agent. ADCT-402 was investigated in a phase I trial ( NCT02669264 ) of adult patients with R/R B-cell ALL. The interim result showed that only two out of 23 patients (8.7%) achieved CR with MRD negativity. The most frequently reported TEAEs were nausea (30%), fatigue (26%), and febrile neutropenia (22%), with febrile neutropenia being the most common SAE [ 112 ]. Another ongoing phase I trial ( NCT02669017 ) of ADCT-402 in R/R B cell NHL recently reported its interim result. ADCT-402 yielded a 40.2% ORR (22% CR), with a median DOR and PFS of 4.17 and 2.79 months respectively at doses > 120 μg/kg in a subpopulation of 132 evaluable patients with R/R DLBCL. Most common SAEs were neutropenia (42%), thrombocytopenia (27.3%), anemia (11.7%), and increased gamma-glutamyltransferase (GGT) (8.8%) [ 113 ]. Among the 132 patients, 15 evaluable patients with mantle cell lymphoma (MCL) treated with ADCT-402 achieved a 46.7% ORR (26.7% CR) and a median DOR and PFS of 5.3 and 4.8 months respectively; while for the 15 evaluable patients with FL, ADCT-402 therapy achieved an 80% ORR (53.3% CR), the median DOR and PFS have not been reached at the 7.56-months follow-up. The most common SAEs were elevated GGT (26.7%), neutropenia (20%), and anemia (13.3%) [ 114 ]. Another phase II trial ( NCT03589469 ) in patients with R/R DLBCL is ongoing to evaluate the efficacy and safety of single agent ADCT-402. In addition, there are phase II trials looking at the combination therapy of ADCT-402 and ibrutinib ( NCT03684694 ), ADCT-402 and durvalumab, a PD-L1 blocker ( NCT03685344 ) for R/R DLBCL, FL, or MCL.

Anti-CD22 ADCs

Pinatuzumab vedotin (Pina, DCDT2980S) is another anti-CD22 ADC currently under clinical development. Pina is a humanized anti-CD22 IgG1 mAb conjugated to MMAE via a protease-cleavable linker [ 121 ]. Pina has been revealed effective with or without rituximab for R/R DLBCL and R/R indolent NHL by a phase I trial ( NCT01209130 ), but little effect was seen in CLL [ 122 ]. A multicenter phase II trial (ROMULUS, NCT01691898 ) randomized 81 patients with R/R DLBCL and 42 patients with R/R FL to receive rituximab plus either Pina (R-Pina) or polatuzumab vedotin (anti-CD79b ADC, discussed above). The recommended dosage was Pina or Pola 2.4 mg/kg with rituximab 375 mg/m 2 every 21 days up to 1 year or until disease progression or severe toxicity. The regimen of R-Pina generated a 60% ORR (26% CR) and a median PFS of 5.4 months for the DLBCL cohort, whereas a 62% ORR (5% CR) and a median PFS of 12.7 months were seen for the FL cohort. Neutropenia (29%) was the most common SAE. Peripheral neuropathy was a major AE that led to discontinuation of treatment in 21% of patients with DLBCL and 48% of patients with FL [ 103 ].

Anti-CD25 ADCs

CD25 is the α subunit of IL-2 receptor (IL-2Rα) involved in the signal transduction for the growth and survival of immune cells. CD25 overexpression has been found in multiple hematologic malignancies including both HL and NHL, as well as ALL, B cell CLL, HCL, and adult T cell leukemia (ATL) [ 123 ]. Camidanlumab tesirine (ADCT-301) is the first ADC developed targeting CD25. ADCT-301 consists of a humanized IgG1 mAb (HuMax®-TAC) conjugated to a PBD dimer warhead via a protease-cleavable linker. ADCT-301 is being investigated in R/R HL and NHL in a phase I trial ( NCT02432235 ). Among 26 patients with R/R HL who failed prior BV treatment, therapy with ADCT-301 at a dose of 45 μg/kg achieved an 80.8% ORR (50% CR). Median DOR and PFS were 7.7 and 6.7 months, respectively. Major SAEs included GGT elevation (16.7%) and maculopapular rash (13.3%) [ 115 ]. The same trial also enrolled 16 patients with B cell NHL and ten patients with T cell NHL who failed a median of three prior therapies. These patients were treated with ADCT-301 at a dose range of 60–150 μg/kg. The B cell NHL cohort demonstrated a 31.3% ORR (18.8% CR), while the T cell NHL cohort demonstrated a 50% ORR (all PR) [ 116 ]. ADCT-301 has also been evaluated in patients with ALL and acute myeloid leukemia (AML) in another phase I trial ( NCT02588092 ). Even though the safety profile was acceptable, no response has been reported to date [ 124 ].

Anti-CD37 ADCs

CD37 is a member of transmembrane tetraspanin protein family. Similar to CD19, CD37 is almost exclusively expressed on B cells, but absent from hematopoietic stem cells and plasma cells. It plays a role in signal transduction and immune cell interactions that are important for B cell activation and survival [ 125 ]. CD37 is also highly expressed on malignant B cells including most histological subtypes of NHL [ 126 ]. Two ADCs targeting CD37, IMGN529 and AGS67E, are currently under clinical development.

Naratuximab emtansine (IMGN529) is a humanized anti-CD37 IgG1 antibody conjugated to the maytansinoid DM1 via a nonreducible thioether linker, succinimidyl-4-( N -maleimidomethyl)-cyclohexane-1-carboxylate (SMCC) [ 127 ]. Of note, IMGN529 exhibited significant intrinsic ADCC activity against targeted cells [ 128 ]. A phase I trial ( NCT01534715 ) evaluated the safety and efficacy of IMGN529 monotherapy with escalating doses in R/R B cell NHL. The MTD was 1.4 mg/kg every 3 weeks. Only five out of 39 (13%) evaluable patients achieved ORR (one CR), four of whom were patients with DLBCL. The most common AEs were neutropenia (37%), thrombocytopenia (37%), and pyrexia (37%) [ 117 ]. Rituximab has been reported to potentiate the antitumor effect of IMGN529 in multiple xenograft models [ 128 ]. The combination of IMGN529 and rituximab for patients with R/R NHL is being explored in a phase II trial ( NCT02564744 ).

AGS67E is a fully human anti-CD37 IgG2 mAb conjugated to MMAE via a protease-cleavable linker. Preclinical study discovered that AGS67E was able to alter cell cycle and induce apoptosis in vitro and in xenograft models of NHL [ 129 ]. AGS67E demonstrated some effects in a phase I trial ( NCT02175433 ) in 50 patients with R/R B and T cell NHL. Eleven (22%) patients experienced ORR, and seven (14%) patients achieved CR, four of whom had DLBCL. Peripheral neuropathy (16%) and neutropenia (8%) were the major AEs [ 118 ].

Anti-CD70 ADCs

CD70, also known as CD27L, is a member of TNF receptor superfamily. The interaction between CD70 and CD27 is critical for B cell activation, T helper 1 (Th1)/Th2 switching, and cell differentiation. CD70 is highly expressed on several malignancies including NHL and renal cell carcinoma (RCC) [ 130 ]. Three anti-CD70 ADCs have been investigated in phase I trials in patients with CD70-positive R/R B-cell NHL and metastatic RCC.

SGN-CD70A is a humanized anti-CD70 IgG1 mAb conjugated to a PBD dimer via a protease-cleavable linker. Severe (grade ≥ 3) early-onset thrombocytopenia was reported in 75% of patients with DLBCL and MCL treated by SGN-CD70A and led to treatment termination ( NCT02216890 ) [ 131 ]. MDX-1203 (BMS-936561) consists of a fully human anti-CD70 IgG1 mAb conjugated to a duocarmycin derivative through a protease-cleavable linker. In a dose-escalation phase I trial ( NCT00944905 ), dose-limiting toxicity of grade 3 hypersensitivity (13%) and delayed toxicities featured by facial edema and pleural/pericardial effusions (38%) were recorded. Eighteen of 26 patients (69%) maintained stable diseases. There was no dose-response correlation [ 132 ]. Vorsetuzumab mafodotin (SGN-75) is a humanized anti-CD70 IgG1 mAb conjugated to MMAF via a non-cleavable linker. However, the development of SGN-75 for NHL was discontinued due to idiopathic thrombocytopenia purpura in two out of 19 NHL patients in a phase I trial ( NCT01015911 ) [ 133 ]. It appears that these three anti-CD70 ADCs have major concerns over the toxicity profiles which led to termination of further clinical development.

ADCs under clinical development for multiple myeloma

Anti-CD56 ADC

CD56, also called neural cell adhesion molecule 1 (NCAM1), is a marker for cells of neuroendocrine origin, as well as natural killer cells and a subset of T cells. It is also expressed on 75% of malignant plasma cells but less than 15% of normal plasma cells. These features make it an attractive therapeutic target for multiple myeloma (MM) [ 134 ]. Lorvotuzumab mertansine (IMGN901) is a humanized anti-CD56 IgG1 mAb conjugated to DM1 via a stable disulfide linker. IMGN901 retains the ADCC activity [ 135 ] (Table 3 ). Single-agent IMGN901 has been evaluated in patients with CD56-positive MM and small-cell lung cancer. In a dose-escalating phase I trial ( NCT00346255 ) that enrolled 37 patients with R/R MM, there was only a 5.7% ORR with no CR, but 42.9% of patients remained in stable disease for an average duration of 15.5 months. The AE profile was acceptable, with the MTD at 112 mg/m 2 [ 136 ]. IMGN901 is being studied in combination with lenalidomide and dexamethasone in a phase I trial ( NCT00991562 ) in patients with R/R MM. Among 32 patients, the ORR was 59% with 1 CR [ 140 ]. Table 3 Antibody-drug conjugates in clinical trials for multiple myeloma ADC names Target Linker Payload Disease Major responses Status [reference] Lorvotuzumab mertansine (IMGN901) CD56 Disulfide bond (SPP) DM1 R/R MM ORR 5.7%, CR 0; 42.9% stable disease for 15.5 mo Phase I [ 136 ] Milatuzumab doxorubicin (hLL1-DOX) CD74 Acid-labile (hydrazine) Doxorubicin R/R MM Data not reported Phase I [ 137 ] Indatuximab ravtansine (BT062) CD138 Disulfide bond (SPDB) DM4 R/R MM ORR 5.9%, CR 0, stable disease 61.8%, OS 26.7 mo, PFS 3 mo Phase I/II [ 138 ] GSK2857916 CD269 (BCMA) Non-cleavable (MC) MMAF R/R MM ORR 60%, CR 14%, PFS 12 mo, DOR 14.3 mo Phase I [ 139 ] ADC antibody-drug conjugate, BCMA B cell maturation antigen, R / R relapsed /refractory, MM multiple myeloma, CR complete remission, DOR duration of response, ORR overall response rate, OS overall survival, PFS progression free survival, Mo month

Anti-CD74 ADC

CD74 is a type II transmembrane glycoprotein involved in major histocompatibility complex class II antigen presentation, B cell maturation, and T cell response. CD74 is expressed in more than 90% of B cell malignancies. It becomes an attractive therapeutic target because of its rapid internalization and recycling [ 141 ]. Milatuzumab doxorubicin (hLL1-DOX) is a humanized CD74 mAb conjugated to doxorubicin via an acid-labile hydrazone linker [ 137 ]. Unconjugated milatuzumab effectively maintained five out of 19 patients with MM (26%) in stable disease for more than 3 months in a phase I trial ( NCT00421525 ) [ 142 ]. hLL1-DOX has been administered to 17 patients with R/R MM in a phase I trial ( NCT01101594 ) which has not reported any updates so far.

Anti-CD138 ADC

CD138, also known as syndecan-1, is a transmembrane protein receptor for extracellular matrix involved in cell-cell adhesion. It is upregulated on malignant plasma cells, as well as various epithelial neoplasms [ 143 ]. Indatuximab ravtansine (BT062) is a chimeric B-B4, an afucosylated IgG4 mAb specific for CD138, conjugated to maytansinoid DM4 via a SPDB disulfide cleavable linker. Preclinical studies have demonstrated the efficacy of BT062 against the growth of MM cells in vivo [ 144 ]. In a phase I trial ( NCT01001442 ) conducted in 35 patients with R/R MM who have failed previous immunomodulatory drugs and proteasome inhibitor therapies, BT062 was administered at the MTD of 140 mg/m 2 on days 1, 8, and 15 of each 28-day cycle. The therapy resulted in a 5.9% ORR with no CR. Then, 61.8% of patients achieved stable diseases. The median OS and PFS were 26.7 and 3 months respectively. Eight-eight percent reported AEs were grade 1–2, with the most common ones being fatigue (47.7%) and diarrhea (43.2%) [ 138 ]. The same regimen was investigated in combination with dexamethasone (20–40 mg on days 1, 8, 15, and 22) and lenalidomide (25 mg, daily on days 1–21) in another phase I/IIa trial ( NCT01638936 ). Among 43 evaluable patients who completed at least 2 cycles of treatment, 33 (77%) achieved ORR (no CR) with a median DOR of 21.0 months. Frequently reported AEs were fatigue, diarrhea, and nausea [ 145 ].

Anti-CD269 (BCMA) ADC

CD269, also known as B cell maturation antigen (BCMA), is a transmembrane receptor required for B cell maturation. It is universally expressed on malignant plasma cells. Increased plasma level of BCMA is associated with a worse prognosis of MM [ 146 , 147 ]. GSK2857916 is a humanized anti-BCMA IgG1 mAb conjugated to MMAF via a MC non-cleavable linker. Additionally, GSK2857916 is able to induce enhanced activity of ADCC against MM cells [ 148 ]. A multicenter phase I trial ( NCT02064387 ) enrolled 35 adult patients with R/R MM after ASCT, alkylators, proteasome inhibitors, and immunomodulators. At a recommended dose of 3.4 mg/kg, 21 (60%) patients showed ORR with 5 (14%) achieving CR in a recent update. The median PFS and DOR were 12 and 14.3 months respectively. There were mostly grade 1-2 AEs, with thrombocytopenia (35%) being the most common SAE. Corneal events such as blurry vision (52%), dry eyes (37%), and photophobia (29%) were reported [ 139 ]. Several phase II trials are currently recruiting to investigate combination regimens incorporating GSK2857916 for patients with R/R MM. One study is exploring GSK2857916 plus pembrolizumab ( NCT03848845 ). Another ongoing study is looking at GSK2857916 administered in combination with dexamethasone plus either lenalidomide or bortezomib ( NCT03544281 ).

Future perspectives

Careful clinical trials are needed for ADCs since several clinical trials of new ADCs have been terminated due to minimal efficacy and unacceptable toxicity. Efforts are being made on identifying better target antigens exclusively expressed on tumor cells to increase the specificity for targeted killing; exploring more potent payloads with high penetration ability and better bystander effect to enhance the antitumor activity; and optimizing the linker and conjugation technology to achieve a homogeneous DAR to enhance drug stability and minimize off-target toxicity. In addition, it is important to discover payloads that can avoid organ-specific toxicity, such as ozogamicin-related hepatic VOD.

A variety of antigen targets used for ADCs, such as CD19, CD22, and BCMA, are also being explored for engineering bispecific antibodies (BiTE) and chimeric antigen receptors (CAR) [ 149 – 153 ]. A CD 19 BiTE, blinatumomab, and two CAR T cell products have been approved for acute lymphoblastic leukemia [ 154 , 155 ]. It remains to be determined whether any particular target (CD19, CD22, or BCMA) or form of targeted agents (ADC, BiTE, or CAR T) offers better therapeutic index. It is equally intriguing whether these immunotargeted agents can be combined concurrently or consequentially.

Conclusion

Proper selections of antigen targets, linkers, and payloads are critical in ADC designs. Robust antitumor activity and favorable toxicity profiles of ADCs have made them an important modality of cancer therapy. ADCs in combination with chemotherapy regimens and immune checkpoint inhibitors are in clinical trials to further improve the treatment of lymphoid malignancies as well as multiple myeloma.

Abbreviations

Antibody-dependent cytotoxicity

Alanine

Citrulline

Complement-dependent cytotoxicity

Dose-limiting toxicity

N20-deacetyl-N20-(3-mercapto-1-oxopropyl)maytansine

N20-deacetyl-N20-(4-mercapto-4-methyl-1-oxopentyl)maytansine

Maleimidocaproyl

Monomethyl auristatin E

Monomethyl auristatin F

Pyrrolobenzodiazepines

Pseudomonas aeruginosa exotoxin

Succinimidyl-4-( N -maleimidomethyl)cyclohexane-1-carboxylate

N -Succinimidyl-4-(2-pyridylthio)butanoate

N -Succinimidyl-4-(2-pyridyldithio)pentanoate

Valine

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgement

We thank Dr. Juanjuan Zhao for her assistance in preparation of Fig. 1 .

Authors’ contributions

DL designed the study. DL and BY drafted the manuscript. All authors participated in the revision of the manuscript. All authors read and approved the final manuscript.

Funding

The study is partly supported by the Affiliated First Hospital of Zhengzhou University, Zhengzhou, China.

Availability of data and materials

The material supporting the conclusion of this review has been included within the article.

Ethics approval and consent to participate

This is not applicable for this review.

Consent for publication

This is not applicable for this review.

Competing interests

The authors have no relevant conflicts.

References

1. Ruan J Martin P Shah B Schuster SJ Smith SM Furman RR Christos P Rodriguez A Svoboda J Lewis J Katz O Coleman M Leonard JP Lenalidomide plus Rituximab as initial treatment for mantle-cell lymphoma New England Journal of Medicine 2015 373 19 1835 1844 10.1056/NEJMoa1505237 26535512 PMC4710541

2. Marcus R Davies A Ando K Klapper W Opat S Owen C Phillips E Sangha R Schlag R Seymour JF Townsend W Trněný M Wenger M Fingerle-Rowson G Rufibach K Moore T Herold M Hiddemann W Obinutuzumab for the first-line treatment of follicular lymphoma New England Journal of Medicine 2017 377 14 1331 1344 10.1056/NEJMoa1614598 28976863

3. Chen RW Palmer JM Tomassetti S Popplewell LL Alluin J Chomchan P Nademanee AP Siddiqi T Tsai N-C Chen L Zuo F Abary R Cai J-l, Herrera AF, Rossi JJ, Rosen ST, Forman SJ, Kwak LW, Holmberg LA: Multi-center phase II trial of bortezomib and rituximab maintenance combination therapy in patients with mantle cell lymphoma after consolidative autologous stem cell transplantation Journal of Hematology & Oncology 2018 11 1 87 10.1186/s13045-018-0631-3 29954415 PMC6022297

4. Steiner RE Romaguera J Wang M Current trials for frontline therapy of mantle cell lymphoma Journal of Hematology & Oncology 2018 11 1 13 10.1186/s13045-018-0556-x 29374487 PMC5787314

5. Perini GF Ribeiro GN Pinto Neto JV Campos LT Hamerschlak N BCL-2 as therapeutic target for hematological malignancies Journal of Hematology & Oncology 2018 11 1 65 10.1186/s13045-018-0608-2 29747654 PMC5946445

6. Epperla N Ahn KW Ahmed S Jagasia M DiGilio A Devine SM Jaglowski S Kennedy V Rezvani AR Smith SM Sureda A Fenske TS Kharfan-Dabaja MA Armand P Hamadani M Rituximab-containing reduced-intensity conditioning improves progression-free survival following allogeneic transplantation in B cell non-Hodgkin lymphoma Journal of Hematology & Oncology 2017 10 1 117 10.1186/s13045-017-0487-y 28606176 PMC5469142

7. Nejadmoghaddam MR Minai-Tehrani A Ghahremanzadeh R Mahmoudi M Dinarvand R Zarnani AH Antibody-drug conjugates: possibilities and challenges Avicenna J Med Biotechnol 2019 11 1 3 23 30800238 PMC6359697

8. Younes A Gopal AK Smith SE Ansell SM Rosenblatt JD Savage KJ Ramchandren R Bartlett NL Cheson BD de Vos S Forero-Torres A Moskowitz CH Connors JM Engert A Larsen EK Kennedy DA Sievers EL Chen R Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma J Clin Oncol 2012 30 18 2183 2189 10.1200/JCO.2011.38.0410 22454421 PMC3646316

9. Yurkiewicz IR Muffly L Liedtke M Inotuzumab ozogamicin: a CD22 mAb-drug conjugate for adult relapsed or refractory B-cell precursor acute lymphoblastic leukemia Drug Des Devel Ther 2018 12 2293 2300 10.2147/DDDT.S150317 30087554 PMC6063246

10. DeAngelo DJ Stock W Stein AS Shustov A Liedtke M Schiffer CA Vandendries E Liau K Ananthakrishnan R Boni J Laird AD Fostvedt L Kantarjian HM Advani AS Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study Blood Adv 2017 1 15 1167 1180 10.1182/bloodadvances.2016001925 29296758 PMC5728308

11. Aujla A Aujla R Liu D Inotuzumab ozogamicin in clinical development for acute lymphoblastic leukemia and non-Hodgkin lymphoma Biomarker Research 2019 7 1 9 10.1186/s40364-019-0160-4 31011424 PMC6458768

12. Chari RV Miller ML Widdison WC Antibody-drug conjugates: an emerging concept in cancer therapy Angew Chem Int Ed Engl 2014 53 15 3796 3827 10.1002/anie.201307628 24677743

13. Denning C Pitts JD Bystander effects of different enzyme-prodrug systems for cancer gene therapy depend on different pathways for intercellular transfer of toxic metabolites, a factor that will govern clinical choice of appropriate regimes Hum Gene Ther 1997 8 15 1825 1835 10.1089/hum.1997.8.15-1825 9358032

14. Kovtun YV Audette CA Ye Y Xie H Ruberti MF Phinney SJ Leece BA Chittenden T Blattler WA Goldmacher VS Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen Cancer Res 2006 66 6 3214 3221 10.1158/0008-5472.CAN-05-3973 16540673

15. Zhang A Fang J Chou RY Bondarenko PV Zhang Z Conformational difference in human IgG2 disulfide isoforms revealed by hydrogen/deuterium exchange mass spectrometry Biochemistry 2015 54 10 1956 1962 10.1021/bi5015216 25730439

16. Peters C Brown S Antibody-drug conjugates as novel anti-cancer chemotherapeutics Bioscience Reports 2015 35 4 e00225 10.1042/BSR20150089 26182432 PMC4613712

17. Schlothauer T Herter S Koller CF Grau-Richards S Steinhart V Spick C Kubbies M Klein C Umana P Mossner E Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions Protein Eng Des Sel 2016 29 10 457 466 10.1093/protein/gzw040 27578889

18. Wiggins B Liu-Shin L Yamaguchi H Ratnaswamy G Characterization of cysteine-linked conjugation profiles of immunoglobulin G1 and immunoglobulin G2 antibody-drug conjugates Journal of Pharmaceutical Sciences 2015 104 4 1362 1372 10.1002/jps.24338 25631158

19. Prabhu S Boswell CA Leipold D Khawli LA Li D Lu D Theil FP Joshi A Lum BL Antibody delivery of drugs and radionuclides: factors influencing clinical pharmacology Ther Deliv 2011 2 6 769 791 10.4155/tde.11.41 22822508

20. Abdollahpour-Alitappeh M Lotfinia M Gharibi T Mardaneh J Farhadihosseinabadi B Larki P Faghfourian B Sepehr KS Abbaszadeh-Goudarzi K Abbaszadeh-Goudarzi G Johari B Zali MR Bagheri N Antibody-drug conjugates (ADCs) for cancer therapy: Strategies, challenges, and successes J Cell Physiol 2019 234 5 5628 5642 10.1002/jcp.27419 30478951

21. Xie H Adjei AA Antibody-drug conjugates for the therapy of thoracic malignancies J Thorac Oncol 2019 14 3 358 376 10.1016/j.jtho.2018.11.034 30599202

22. Hamblett KJ Senter PD Chace DF Sun MM Lenox J Cerveny CG Kissler KM Bernhardt SX Kopcha AK Zabinski RF Meyer DL Francisco JA Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate Clin Cancer Res 2004 10 20 7063 7070 10.1158/1078-0432.CCR-04-0789 15501986

23. Nittoli T Kelly MP Delfino F Rudge J Kunz A Markotan T Spink J Chen Z Shan J Navarro E Tait M Provoncha K Giurleo J Zhao F Jiang X Hylton D Makonnen S Hickey C Kirshner JR Thurston G Papadopoulos N Antibody drug conjugates of cleavable amino-alkyl and aryl maytansinoids Bioorg Med Chem 2018 26 9 2271 2279 10.1016/j.bmc.2018.02.025 29605304

24. Cunningham D Parajuli KR Zhang C Wang G Mei J Zhang Q Liu S You Z Monomethyl Auristatin E Phosphate inhibits human prostate cancer growth Prostate 2016 76 15 1420 1430 10.1002/pros.23226 27325602 PMC5033698

25. Gebleux R Stringhini M Casanova R Soltermann A Neri D Non-internalizing antibody-drug conjugates display potent anti-cancer activity upon proteolytic release of monomethyl auristatin E in the subendothelial extracellular matrix Int J Cancer 2017 140 7 1670 1679 10.1002/ijc.30569 27943268 PMC5606289

26. Li H Yu C Jiang J Huang C Yao X Xu Q Yu F Lou L Fang J An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer Cancer Biol Ther 2016 17 4 346 354 10.1080/15384047.2016.1139248 26853765 PMC4910924

27. Sochaj-Gregorczyk AM Serwotka-Suszczak AM Otlewski J A novel affibody-auristatin E conjugate with a potent and selective activity against HER2+ cell lines J Immunother 2016 39 6 223 232 10.1097/CJI.0000000000000125 27227324

28. Sommer A Kopitz C Schatz CA Nising CF Mahlert C Lerchen HG Stelte-Ludwig B Hammer S Greven S Schuhmacher J Braun M Zierz R Wittemer-Rump S Harrenga A Dittmer F Reetz F Apeler H Jautelat R Huynh H Ziegelbauer K Kreft B Preclinical efficacy of the auristatin-based antibody-drug conjugate BAY 1187982 for the Treatment of FGFR2-Positive Solid Tumors Cancer Res 2016 76 21 6331 6339 10.1158/0008-5472.CAN-16-0180 27543601

29. Waight AB Bargsten K Doronina S Steinmetz MO Sussman D Prota AE: structural basis of microtubule destabilization by potent auristatin anti-mitotics PLoS One 2016 11 8 e0160890 10.1371/journal.pone.0160890 27518442 PMC4982639

30. Woitok M Klose D Niesen J Richter W Abbas M Stein C Fendel R Bialon M Puttmann C Fischer R Barth S Kolberg K: the efficient elimination of solid tumor cells by EGFR-specific and HER2-specific scFv-SNAP fusion proteins conjugated to benzylguanine-modified auristatin F Cancer Lett 2016 381 2 323 330 10.1016/j.canlet.2016.08.003 27502168

31. Yoshida S Tuscano E Duong C Chung J Li Y Beckett L Tuscano JM Satake N Efficacy of an anti-CD22 antibody-monomethyl auristatin E conjugate in a preclinical xenograft model of precursor B-cell acute lymphoblastic leukemia Leuk Lymphoma 2017 58 5 1254 1257 10.1080/10428194.2016.1235273 27701909 PMC5457839

32. Vezina HE Cotreau M Han TH Gupta M Antibody-drug conjugates as cancer therapeutics: past, present, and future J Clin Pharmacol 2017 57 Suppl 10 S11 S25 10.1002/jcph.981 28921650

33. Jackson PJM Kay S Pysz I Thurston DE Use of pyrrolobenzodiazepines and related covalent-binding DNA-interactive molecules as ADC payloads: is mechanism related to systemic toxicity? Drug Discov Today Technol 2018 30 71 83 10.1016/j.ddtec.2018.10.004 30553523

34. Yang X Wang J Precision therapy for acute myeloid leukemia Journal of Hematology & Oncology 2018 11 1 3 10.1186/s13045-017-0543-7 29301553 PMC5755341

35. Saygin C Carraway HE Emerging therapies for acute myeloid leukemia Journal of Hematology & Oncology 2017 10 1 93 10.1186/s13045-017-0463-6 28420416 PMC5395764

36. Wynne J Wright D Stock W Inotuzumab: from preclinical development to success in B-cell acute lymphoblastic leukemia Blood Adv 2019 3 1 96 104 10.1182/bloodadvances.2018026211 30622147 PMC6325303

37. Tsuchikama K An Z Antibody-drug conjugates: recent advances in conjugation and linker chemistries Protein Cell 2018 9 1 33 46 10.1007/s13238-016-0323-0 27743348 PMC5777969

38. Dubowchik GM Firestone RA Padilla L Willner D Hofstead SJ Mosure K Knipe JO Lasch SJ Trail PA Cathepsin B-labile dipeptide linkers for lysosomal release of doxorubicin from internalizing immunoconjugates: model studies of enzymatic drug release and antigen-specific in vitro anticancer activity Bioconjug Chem 2002 13 4 855 869 10.1021/bc025536j 12121142

39. Saito G Swanson JA Lee KD Drug delivery strategy utilizing conjugation via reversible disulfide linkages: role and site of cellular reducing activities Adv Drug Deliv Rev 2003 55 2 199 215 10.1016/S0169-409X(02)00179-5 12564977

40. Lu Jun Jiang Feng Lu Aiping Zhang Ge Linkers Having a Crucial Role in Antibody–Drug Conjugates International Journal of Molecular Sciences 2016 17 4 561 10.3390/ijms17040561 27089329 PMC4849017

41. Lazar AC Wang LT Blattler WA Amphlett G Lambert JM Zhang W Analysis of the composition of immunoconjugates using size-exclusion chromatography coupled to mass spectrometry Rapid Communications in Mass Spectrometry 2005 19 13 1806 1814 10.1002/rcm.1987 15945030

42. Junutula JR Raab H Clark S Bhakta S Leipold DD Weir S Chen Y Simpson M Tsai SP Dennis MS Lu Y Meng YG Ng C Yang J Lee CC Duenas E Gorrell J Katta V Kim A McDorman K Flagella K Venook R Ross S Spencer SD Lee Wong W Lowman HB Vandlen R Sliwkowski MX Scheller RH Polakis P Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index Nat Biotechnol 2008 26 8 925 932 10.1038/nbt.1480 18641636

43. Axup JY Bajjuri KM Ritland M Hutchins BM Kim CH Kazane SA Halder R Forsyth JS Santidrian AF Stafin K Lu YC Tran H Seller AJ Biroce SL Szydlik A Pinkstaff JK Tian F Sinha SC Felding-Habermann B Smider VV Schultz PG Synthesis of site-specific antibody-drug conjugates using unnatural amino acids Proceedings of the National Academy of Sciences of the United States of America 2012 109 40 16101 16106 10.1073/pnas.1211023109 22988081 PMC3479532

44. Zimmerman ES Heibeck TH Gill A Li X Murray CJ Madlansacay MR Tran C Uter NT Yin G Rivers PJ Yam AY Wang WD Steiner AR Bajad SU Penta K Yang W Hallam TJ Thanos CD Sato AK Production of site-specific antibody-drug conjugates using optimized non-natural amino acids in a cell-free expression system Bioconjug Chem 2014 25 2 351 361 10.1021/bc400490z 24437342

45. Antos JM Ingram J Fang T Pishesha N Truttmann MC Ploegh HL Site-Specific Protein Labeling via Sortase-Mediated Transpeptidation Curr Protoc Protein Sci 2017 89 1531 15319 10.1002/cpps.38 PMC5810355 28762490

46. Jeger S Zimmermann K Blanc A Grunberg J Honer M Hunziker P Struthers H Schibli R Site-specific and stoichiometric modification of antibodies by bacterial transglutaminase Angew Chem Int Ed Engl 2010 49 51 9995 9997 10.1002/anie.201004243 21110357

47. Zhou Q Stefano JE Manning C Kyazike J Chen B Gianolio DA Park A Busch M Bird J Zheng XY Simonds-Mannes H Kim J Gregory RC Miller RJ Brondyk WH Dhal PK Pan CQ: Site-specific Antibody-drug conjugation through glycoengineering. bioconjugate chemistry 2014 25 3 510 520 24533768 10.1021/bc400505q

48. Sutherland MS Sanderson RJ Gordon KA Andreyka J Cerveny CG Yu C Lewis TS Meyer DL Zabinski RF Doronina SO Senter PD Law CL Wahl AF Lysosomal trafficking and cysteine protease metabolism confer target-specific cytotoxicity by peptide-linked anti-CD30-auristatin conjugates J Biol Chem 2006 281 15 10540 10547 10.1074/jbc.M510026200 16484228

49. Wang Y Nowakowski GS Wang ML Ansell SM Advances in CD30- and PD-1-targeted therapies for classical Hodgkin lymphoma Journal of Hematology & Oncology 2018 11 1 57 10.1186/s13045-018-0601-9 29685160 PMC5914042

50. Schirrmann T Steinwand M Wezler X Ten Haaf A Tur MK Barth S CD30 as a therapeutic target for lymphoma BioDrugs 2014 28 2 181 209 10.1007/s40259-013-0068-8 24043362

51. Connors JM Jurczak W Straus DJ Ansell SM Kim WS Gallamini A Younes A Alekseev S Illes A Picardi M Lech-Maranda E Oki Y Feldman T Smolewski P Savage KJ Bartlett NL Walewski J Chen R Ramchandren R Zinzani PL Cunningham D Rosta A Josephson NC Song E Sachs J Liu R Jolin HA Huebner D Radford J Group E-S Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma N Engl J Med 2018 378 4 331 344 10.1056/NEJMoa1708984 29224502 PMC5819601

52. Younes A Bartlett NL Leonard JP Kennedy DA Lynch CM Sievers EL Forero-Torres A Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas New England Journal of Medicine 2010 363 19 1812 1821 10.1056/NEJMoa1002965 21047225

53. Gopal AK Chen R Smith SE Ansell SM Rosenblatt JD Savage KJ Connors JM Engert A Larsen EK Chi X Sievers EL Younes A Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma Blood 2015 125 8 1236 1243 10.1182/blood-2014-08-595801 25533035 PMC4335079

54. Chen R Gopal AK Smith SE Ansell SM Rosenblatt JD Savage KJ Connors JM Engert A Larsen EK Huebner D Fong A Younes A Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma Blood 2016 128 12 1562 1566 10.1182/blood-2016-02-699850 27432875 PMC5034737

55. Chen RW Chen L Herrera AF Mei M McBride K Abary R Siddiqi T Popplewell L Forman SJ Rosen ST Kwak LW Phase 1 Study of MDR1 inhibitor plus brentuximab vedotin in relapsed/refractory Hodgkin lymphoma Blood 2018 132 Suppl 1 1636

56. O'Connor OA Lue JK Sawas A Amengual JE Deng C Kalac M Falchi L Marchi E Turenne I Lichtenstein R Rojas C Francescone M Schwartz L Cheng B Savage KJ Villa D Crump M Prica A Kukreti V Cremers S Connors JM Kuruvilla J Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin's lymphoma: an international, multicentre, single-arm, phase 1-2 trial Lancet Oncol 2018 19 2 257 266 10.1016/S1470-2045(17)30912-9 29276022 PMC9098158

57. LaCasce AS Bociek RG Sawas A Caimi P Agura E Matous J Ansell SM Crosswell HE Islas-Ohlmayer M Behler C Cheung E Forero-Torres A Vose J O'Connor OA Josephson N Wang Y Advani R Brentuximab vedotin plus bendamustine: a highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma Blood 2018 132 1 40 48 10.1182/blood-2017-11-815183 29703778 PMC6073588

58. Sawas A, Kuruvilla J, Lue JK, Deng CC, Amengual JE, Montanari F, Savage KJ, Elgedawe H, Villa D, Crump M, Connors JM, O'Connor OA: Prolonged overall survival (OS) in a subset of responders to the combination of brentuximab vedotin (Bv) and bendamustine (B) in heavily treated patients with relapsed or refractory Hodgkin lymphoma (HL): results of an international multi- center phase I/II experience. Blood 2018, 132:2908.

59. Herrera AF Moskowitz AJ Bartlett NL Vose JM Ramchandren R Feldman TA LaCasce AS Ansell SM Moskowitz CH Fenton K Ogden CA Taft D Zhang Q Kato K Campbell M Advani RH Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma Blood 2018 131 11 1183 1194 10.1182/blood-2017-10-811224 29229594 PMC5855021

60. Moskowitz CH Nademanee A Masszi T Agura E Holowiecki J Abidi MH Chen AI Stiff P Gianni AM Carella A Osmanov D Bachanova V Sweetenham J Sureda A Huebner D Sievers EL Chi A Larsen EK Hunder NN Walewski J Group AS Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial Lancet 2015 385 9980 1853 1862 10.1016/S0140-6736(15)60165-9 25796459

61. Moskowitz CH Walewski J Nademanee A Masszi T Agura E Holowiecki J Abidi MH Chen AI Stiff P Viviani S Bachanova V Sureda A McClendon T Lee C Lisano J Sweetenham J Five-year PFS from the AETHERA trial of brentuximab vedotin for Hodgkin lymphoma at high risk of progression or relapse Blood 2018 132 25 2639 2642 10.1182/blood-2018-07-861641 30266774

62. Gaudio F Mazza P Mele A Palazzo G Carella AM Delia M Pisapia G Pastore D Cascavilla N Pavone V Specchia G Brentuximab vedotin prior to allogeneic stem cell transplantation increases survival in chemorefractory Hodgkin's lymphoma patients Ann Hematol 2019 98 6 1449 1455 10.1007/s00277-019-03662-6 30868307

63. Connors JM Younes A Gallamini A Brentuximab vedotin plus chemotherapy in patients with advanced-stage classical hodgkin lymphoma: evaluation of modified progression-free survival and traditional PFS in the phase 3 ECHELON-1 study Clinical Advances in Hematology & Oncology 2019 17 2 19 20

64. Eichenauer DA Plutschow A Kreissl S Sokler M Hellmuth JC Meissner J Mathas S Topp MS Behringer K Klapper W Kuhnert G Dietlein M Kobe C Fuchs M Diehl V Engert A Borchmann P Incorporation of brentuximab vedotin into first-line treatment of advanced classical Hodgkin's lymphoma: final analysis of a phase 2 randomised trial by the German Hodgkin Study Group Lancet Oncology 2017 18 12 1680 1687 10.1016/S1470-2045(17)30696-4 29133014

65. Pro B Advani R Brice P Bartlett NL Rosenblatt JD Illidge T Matous J Ramchandren R Fanale M Connors JM Yang Y Sievers EL Kennedy DA Shustov A Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study J Clin Oncol 2012 30 18 2190 2196 10.1200/JCO.2011.38.0402 22614995

66. Pro B Advani R Brice P Bartlett NL Rosenblatt JD Illidge T Matous J Ramchandren R Fanale M Connors JM Fenton K Huebner D Pinelli JM Kennedy DA Shustov A Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma Blood 2017 130 25 2709 2717 10.1182/blood-2017-05-780049 28974506 PMC5746164

67. Horwitz S, O'Connor OA, Pro B, Illidge T, Fanale M, Advani R, Bartlett NL, Christensen JH, Morschhauser F, Domingo-Domenech E, Rossi G, Kim WS, Feldman T, Lennard A, Belada D, Illes A, Tobinai K, Tsukasaki K, Yeh SP, Shustov A, Huttmann A, Savage KJ, Yuen S, Iyer S, Zinzani PL, Hua Z, Little M, Rao S, Woolery J, Manley T et al: Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet 2019, 393(10168):229-240. 10.1016/S0140-6736(18)32984-2 PMC6436818 30522922

68. Prince H Miles Kim Youn H Horwitz Steven M Dummer Reinhard Scarisbrick Julia Quaglino Pietro Zinzani Pier Luigi Wolter Pascal Sanches Jose A Ortiz-Romero Pablo L Akilov Oleg E Geskin Larisa Trotman Judith Taylor Kerry Dalle Stephane Weichenthal Michael Walewski Jan Fisher David Dréno Brigitte Stadler Rudolf Feldman Tatyana Kuzel Timothy M Wang Yinghui Palanca-Wessels Maria Corinna Zagadailov Erin Trepicchio William L Zhang Wenwen Lin Hui-Min Liu Yi Huebner Dirk Little Meredith Whittaker Sean Duvic Madeleine Trotman Judith Joske David Prince H. Miles Taylor Kerry Lewis Ian D. Jonak Constanze Trautinger Franz Bechter Oliver Wolter Pascal Bron Dominique de Lima Vladmir Claudio C. Sanches Jose Antonio Klasa Richard Bagot Martine Beylot-Barry Marie Dalle Stephane D'Incan Michel Dreno Brigitte Grange Florent Nicolay Jan Stadler Rudolf Weichenthal Michael Wobser Marion Assaf Chalid Loquai Carmen Quaglino Pietro Spina Michele Zinzani Pier Luigi Bosi Alberto Fattori Pier Paolo Grzanka Aleksandra Walewski Jan Lopez-Hernandez Andres Ortiz-Romero Pablo L. Roca Jose Juan Rifon Canales Silvana Novelli Dummer Reinhard Illidge Timothy Johnson Rod Whittaker Sean Morris Stephen McKay Pam Scarisbrick Julia Duvic Madeleine Feldman Tatyana Akilov Oleg Geskin Larisa Horwitz Steve Kim Youn H. Pro Barbara Kuzel Timothy Lerner Adam Eradat Herbert Sokol Lubomir Fisher David C. Hughey Sarah Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial The Lancet 2017 390 10094 555 566 10.1016/S0140-6736(17)31266-7 28600132

69. Jacobsen ED Sharman JP Oki Y Advani RH Winter JN Bello CM Spitzer G Palanca-Wessels MC Kennedy DA Levine P Yang J Bartlett NL Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression Blood 2015 125 9 1394 1402 10.1182/blood-2014-09-598763 25573987

70. Zinzani PL Pellegrini C Chiappella A Di Rocco A Salvi F Cabras MG Argnani L Stefoni V Brentuximab vedotin in relapsed primary mediastinal large B-cell lymphoma: results from a phase 2 clinical trial Blood 2017 129 16 2328 2330 10.1182/blood-2017-01-764258 28264798

71. Thota S Advani A Inotuzumab ozogamicin in relapsed B-cell acute lymphoblastic leukemia Eur J Haematol 2017 98 5 425 434 10.1111/ejh.12862 28152223

72. Piccaluga PP Arpinati M Candoni A Laterza C Paolini S Gazzola A Sabattini E Visani G Pileri SA Surface antigens analysis reveals significant expression of candidate targets for immunotherapy in adult acute lymphoid leukemia Leuk Lymphoma 2011 52 2 325 327 10.3109/10428194.2010.529206 21077738

73. Shor Boris Gerber Hans-Peter Sapra Puja Preclinical and clinical development of inotuzumab-ozogamicin in hematological malignancies Molecular Immunology 2015 67 2 107 116 10.1016/j.molimm.2014.09.014 25304309

74. Kantarjian HM DeAngelo DJ Stelljes M Martinelli G Liedtke M Stock W Gokbuget N O'Brien S Wang K Wang T Paccagnella ML Sleight B Vandendries E Advani AS Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia N Engl J Med 2016 375 8 740 753 10.1056/NEJMoa1509277 27292104 PMC5594743

75. Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gokbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019. 10.1002/cncr.32116 PMC6618133 30920645

76. Kantarjian HM Su Y Jabbour EJ Bhattacharyya H Yan E Cappelleri JC Marks DI Patient-reported outcomes from a phase 3 randomized controlled trial of inotuzumab ozogamicin versus standard therapy for relapsed/refractory acute lymphoblastic leukemia Cancer 2018 124 10 2151 2160 10.1002/cncr.31317 29508899

77. Kantarjian HM DeAngelo DJ Advani AS Stelljes M Kebriaei P Cassaday RD Merchant AA Fujishima N Uchida T Calbacho M Ejduk AA O'Brien SM Jabbour EJ Zhang H Sleight BJ Vandendries ER Marks DI Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study Lancet Haematol 2017 4 8 e387 e398 10.1016/S2352-3026(17)30103-5 28687420

78. Kebriaei P Cutler C de Lima M Giralt S Lee SJ Marks D Merchant A Stock W van Besien K Stelljes M Management of important adverse events associated with inotuzumab ozogamicin: expert panel review Bone Marrow Transplant 2018 53 4 449 456 10.1038/s41409-017-0019-y 29330398 PMC5897380

79. Kantarjian H Thomas D Jorgensen J Kebriaei P Jabbour E Rytting M York S Ravandi F Garris R Kwari M Faderl S Cortes J Champlin R O'Brien S Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia Cancer 2013 119 15 2728 2736 10.1002/cncr.28136 23633004 PMC3720844

80. Liu D Zhao J Song Y Luo X Yang T Clinical trial update on bispecific antibodies, antibody-drug conjugates, and antibody-containing regimens for acute lymphoblastic leukemia Journal of Hematology & Oncology 2019 12 1 15 10.1186/s13045-019-0703-z 30736842 PMC6368716

81. Jabbour E Ravandi F Kebriaei P Huang X Short NJ Thomas D Sasaki K Rytting M Jain N Konopleva M Garcia-Manero G Champlin R Marin D Kadia T Cortes J Estrov Z Takahashi K Patel Y Khouri MR Jacob J Garris R O'Brien S Kantarjian H Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD for patients with relapsed or refractory philadelphia chromosome-negative acute lymphoblastic leukemia: a phase 2 clinical trial JAMA Oncol 2018 4 2 230 234 10.1001/jamaoncol.2017.2380 28859185 PMC5838597

82. Kantarjian H Ravandi F Short NJ Huang X Jain N Sasaki K Daver N Pemmaraju N Khoury JD Jorgensen J Alvarado Y Konopleva M Garcia-Manero G Kadia T Yilmaz M Bortakhur G Burger J Kornblau S Wierda W DiNardo C Ferrajoli A Jacob J Garris R O'Brien S Jabbour E Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study Lancet Oncol 2018 19 2 240 248 10.1016/S1470-2045(18)30011-1 29352703 PMC11537312

83. Kantarjian H Stein A Gökbuget N Fielding AK Schuh AC Ribera J-M Wei A Dombret H Foà R Bassan R Arslan Ö Sanz MA Bergeron J Demirkan F Lech-Maranda E Rambaldi A Thomas X Horst H-A Brüggemann M Klapper W Wood BL Fleishman A Nagorsen D Holland C Zimmerman Z Topp MS Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia New England Journal of Medicine 2017 376 9 836 847 10.1056/NEJMoa1609783 28249141 PMC5881572

84. Nägele V Kratzer A Zugmaier G Holland C Hijazi Y Topp MS Gökbuget N Baeuerle PA Kufer P Wolf A Klinger M Changes in clinical laboratory parameters and pharmacodynamic markers in response to blinatumomab treatment of patients with relapsed/refractory ALL Experimental Hematology & Oncology 2017 6 1 14 10.1186/s40164-017-0074-5 28533941 PMC5437652

85. Topp MS Gokbuget N Stein AS Zugmaier G O'Brien S Bargou RC Dombret H Fielding AK Heffner L Larson RA Neumann S Foa R Litzow M Ribera JM Rambaldi A Schiller G Bruggemann M Horst HA Holland C Jia C Maniar T Huber B Nagorsen D Forman SJ Kantarjian HM Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study Lancet Oncol 2014 16 1 57 66 10.1016/S1470-2045(14)71170-2 25524800

86. Zhang X Yang Y Fan D Xiong D The development of bispecific antibodies and their applications in tumor immune escape Experimental Hematology & Oncology 2017 6 1 12 10.1186/s40164-017-0072-7 28469973 PMC5414286

87. Short NJ, Jabbour EJ, Ravandi F, Huang XL, Jain N, Sasaki K, Pemmaraju N, Daver NG, Khoury JD, Jorgensen JL, Alvarado Y, Konopleva MY, Garcia-Manero G, Kadia TM, Yilmaz M, Borthakur G, Burger JA, Kornblau SM, Wierda WG, DiNardo CD, Ferrajoli A, Nasnas P, Jacob J, Garris RE, O'Brien SM, Kantarjian HM: Chemoimmunotherapy with Inotuzumab Ozogamicin Combined with Mini-Hyper-CVD, with or without Blinatumomab, for newly diagnosed older patients with Philadelphia chromosome-negative acute lymphoblastic leukemia: results from a phase II study. Blood 2018, 132(Suppl 1):36.

88. Jabbour EJ, Sasaki K, Ravandi F, Short NJ, Garcia-Manero G, Daver N, Kadia T, Konopleva M, Jain N, Cortes J, Issa GC, Jacob J, Kwari M, Thompson P, Garris R, Pemmaraju N, Yilmaz M, O'Brien SM, Kantarjian HM: Inotuzumab ozogamicin in combination with low-intensity chemotherapy (mini-HCVD) with or without blinatumomab versus standard intensive chemotherapy (HCVAD) as frontline therapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukemia: a propensity score analysis. Cancer 2019, 125:10.1002/cncr.32139. 10.1002/cncr.32139 PMC6625850 30985931

89. Goy A Forero A Wagner-Johnston N Christopher Ehmann W Tsai M Hatake K Ananthakrishnan R Volkert A Vandendries E Ogura M A phase 2 study of inotuzumab ozogamicin in patients with indolent B-cell non-Hodgkin lymphoma refractory to rituximab alone, rituximab and chemotherapy, or radioimmunotherapy Br J Haematol 2016 174 4 571 581 10.1111/bjh.14094 27101934

90. Fayad L Offner F Smith MR Verhoef G Johnson P Kaufman JL Rohatiner A Advani A Foran J Hess G Coiffier B Czuczman M Gine E Durrant S Kneissl M Luu KT Hua SY Boni J Vandendries E Dang NH Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab J Clin Oncol 2013 31 5 573 583 10.1200/JCO.2012.42.7211 23295790 PMC4878046

91. Wagner-Johnston ND Goy A Rodriguez MA Ehmann WC Hamlin PA Radford J Thieblemont C Suh C Sweetenham J Huang Y Sullivan ST Vandendries ER Gisselbrecht C A phase 2 study of inotuzumab ozogamicin and rituximab, followed by autologous stem cell transplant in patients with relapsed/refractory diffuse large B-cell lymphoma Leuk Lymphoma 2015 56 10 2863 2869 10.3109/10428194.2015.1017821 25707288

92. Dang NH Ogura M Castaigne S Fayad LE Jerkeman M Radford J Pezzutto A Bondarenko I Stewart DA Shnaidman M Sullivan S Vandendries E Tobinai K Ramchandren R Hamlin PA Gine E Ando K Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab versus chemotherapy plus rituximab for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma Br J Haematol 2018 182 4 583 586 10.1111/bjh.14820 28677896 PMC6200343

93. Ogura M Tobinai K Hatake K Davies A Crump M Ananthakrishnan R Ishibashi T Paccagnella ML Boni J Vandendries E MacDonald D Phase I study of inotuzumab ozogamicin combined with R-CVP for relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma Clin Cancer Res 2016 22 19 4807 4816 10.1158/1078-0432.CCR-15-2488 27154915

94. Sangha R Davies A Dang NH Ogura M MacDonald DA Ananthakrishnan R Paccagnella ML Vandendries E Boni J Goh YT Phase 1 study of inotuzumab ozogamicin combined with R-GDP for the treatment of patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma J Drug Assess 2017 6 1 10 17 10.1080/21556660.2017.1315336 28959500 PMC5614242

95. Alderson RF Kreitman RJ Chen T Yeung P Herbst R Fox JA Pastan I CAT-8015: a second-generation pseudomonas exotoxin A-based immunotherapy targeting CD22-expressing hematologic malignancies Clin Cancer Res 2009 15 3 832 839 10.1158/1078-0432.CCR-08-1456 19188153 PMC2742326

96. Kreitman RJ Pastan I Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox Clin Cancer Res 2011 17 20 6398 6405 10.1158/1078-0432.CCR-11-0487 22003067 PMC3201735

97. Kreitman RJ Dearden C Zinzani PL Delgado J Karlin L Robak T Gladstone DE le Coutre P Dietrich S Gotic M Larratt L Offner F Schiller G Swords R Bacon L Bocchia M Bouabdallah K Breems DA Cortelezzi A Dinner S Doubek M Gjertsen BT Gobbi M Hellmann A Lepretre S Maloisel F Ravandi F Rousselot P Rummel M Siddiqi T Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia Leukemia 2018 32 8 1768 1777 10.1038/s41375-018-0210-1 30030507 PMC6087717

98. Kreitman RJ Tallman MS Robak T Coutre S Wilson WH Stetler-Stevenson M FitzGerald DJ Santiago L Gao G Lanasa MC Pastan I Minimal residual hairy cell leukemia eradication with moxetumomab pasudotox: phase 1 results and long-term follow-up Blood 2018 131 21 2331 2334 10.1182/blood-2017-09-803072 29487070 PMC5969375

99. Dhillon S Moxetumomab Pasudotox: First Global Approval Drugs 2018 78 16 1763 1767 10.1007/s40265-018-1000-9 30357593 PMC6323103

100. Fichtner M, Dreyling M, Binder M, Trepel M: The role of B cell antigen receptors in mantle cell lymphoma. Journal of Hematology & Oncology 2017, 10(1):164. 10.1186/s13045-017-0533-9 PMC5646121 29041946

101. Pfeifer M Zheng B Erdmann T Koeppen H McCord R Grau M Staiger A Chai A Sandmann T Madle H Dorken B Chu YW Chen AI Lebovic D Salles GA Czuczman MS Palanca-Wessels MC Press OW Advani R Morschhauser F Cheson BD Lenz P Ott G Polson AG Mundt KE Lenz G Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes Leukemia 2015 29 7 1578 1586 10.1038/leu.2015.48 25708834

102. Palanca-Wessels MC Czuczman M Salles G Assouline S Sehn LH Flinn I Patel MR Sangha R Hagenbeek A Advani R Tilly H Casasnovas O Press OW Yalamanchili S Kahn R Dere RC Lu D Jones S Jones C Chu YW Morschhauser F Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study Lancet Oncol 2015 16 6 704 715 10.1016/S1470-2045(15)70128-2 25925619

103. Morschhauser F Flinn IW Advani R Sehn LH Diefenbach C Kolibaba K Press OW Salles G Tilly H Chen AI Assouline S Cheson BD Dreyling M Hagenbeek A Zinzani PL Jones S Cheng J Lu D Penuel E Hirata J Wenger M Chu YW Sharman J Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS) Lancet Haematol 2019 6 5 e254 e265 10.1016/S2352-3026(19)30026-2 30935953

104. Sehn LH Herrera AF Matasar MJ Kamdar M Assouline S Hertzberg M Kim TM Kim WS McMillan A Ozcan M Hirata JM Penuel E Cheng J Ku G Flowers CR Polatuzumab vedotin (Pola) plus bendamustine (B) with rituximab (R) or obinutuzumab (G) in Relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): updated results of a phase (Ph) Ib/II study Blood 2018 132 Suppl 1 1683

105. Forero-Torres A Kolibaba KS Tilly H Salles G Wang LJ Lee C Sharman JP Polatuzumab vedotin combined with obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (G-CHP) for patients with previously untreated diffuse large B-cell lymphoma (DLBCL): updated results of a phase Ib/II study Blood 2017 130 4120

106. Tilly H Sharman J Bartlett N Morschhauser F Haioun C Munoz J Chen A Lamy T Wang L Penuel E Hirata J Lee C Salles G Pola-R-Chp: Polatuzumab Vedotin Combined with Rituximab, Cyclophosphamide, doxorubicin, prednisone for patients with previously untreated diffuse large B-cell lymphoma Haematologica 2017 102 4 4 10.3324/haematol.2016.155267 28040787 PMC5210227

107. Scheuermann RH Racila E CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy Leuk Lymphoma 1995 18 5-6 385 397 10.3109/10428199509059636 8528044

108. Hong EE Erickson H Lutz RJ Whiteman KR Jones G Kovtun Y Blanc V Lambert JM Design of coltuximab ravtansine, a CD19-targeting antibody-drug conjugate (ADC) for the treatment of B-cell malignancies: structure-activity relationships and preclinical evaluation Mol Pharm 2015 12 6 1703 1716 10.1021/acs.molpharmaceut.5b00175 25856201

109. Trnĕný Marek Verhoef Gregor Dyer Martin JS Ben Yehuda Dina Patti Caterina Canales Miguel Lopez Andrés Awan Farrukh T Montgomery Paul G Janikova Andrea Barbui Anna M Sulek Kazimierz Terol Maria J Radford John Guidetti Anna Di Nicola Massimo Siraudin Laure Hatteville Laurence Schwab Sandrine Oprea Corina Gianni Alessandro M A phase II multicenter study of the anti-CD19 antibody drug conjugate coltuximab ravtansine (SAR3419) in patients with relapsed or refractory diffuse large B-cell lymphoma previously treated with rituximab-based immunotherapy Haematologica 2018 103 8 1351 1358 10.3324/haematol.2017.168401 29748443 PMC6068033

110. Fathi AT Borate U DeAngelo DJ O'Brien MM Trippett T Shah BD Hale GA Foran JM Silverman LB Tibes R Cramer S Pauly M Kim S Kostic A Huang XH Pan Y Chen R A phase 1 study of denintuzumab mafodotin (SGN-CD19A) in adults with relapsed or refractory B-lineage acute leukemia (B-ALL) and highly aggressive lymphoma Blood 2015 126 23 1328

111. Moskowitz CH Fanale MA Shah BD Advani RH Chen R Kim S Kostic A Liu TN Peng J Forero-Torres A A phase 1 study of denintuzumab mafodotin (SGN-CD19A) in relapsed/refactory B-lineage non-Hodgkin lymphoma Blood 2015 126 23 182

112. Jain N Klisovic RB Stock W Ungar D Zeidan AM Atallah E McCloskey J Heffner L Tomlinson B Kantarjian HM He S Boni J Wieduwilt MJ Interim data from a phase 1 study evaluating pyrrolobenzodiazepine-based antibody drug conjugate ADCT-402 (Loncastuximab Tesirine) targeting CD19 for relapsed or refractory B-cell acute lymphoblastic leukemia Blood 2017 130 1321 10.1182/blood-2017-03-771576

113. Radford J Kahl BS Hamadani M Carlo-Stella C Caimi P Ardeshna KM Feingold J He S Reid E Solh M Chung KY Heffner L Ungar D O'Connor OA Interim results from the first-in-human clinical trial of Adct-402 (Loncastuximab Tesirine), a novel pyrrolobenzodiazepine-based antibody drug conjugate, in relapsed/refractory diffuse large B-cell lymphoma Blood 2018 132 398

114. Caimi P Kahl BS Hamadani M Carlo-Stella C He S Ungar D Feingold J Ardeshna KM Radford J Solh M Heffner L O'Connor OA Safety and efficacy of Adct-402 (Loncastuximab Tesirine), a novel antibody drug conjugate, in relapsed/refractory follicular lymphoma and mantle cell lymphoma: interim results from the phase 1 first-in-human study Blood 2018 132 2874

115. Hamadani M Collins GP Samaniego F Spira AI Davies A Radford J Caimi P Menne T Boni J Cruz H Feingold J He S Wuerthner J Horwitz SM Phase 1 study of Adct-301 (Camidanlumab Tesirine), a novel pyrrolobenzodiazepine-based antibody drug conjugate, in relapsed/refractory classical Hodgkin lymphoma Blood 2018 132 928

116. Collins GP Horwitz SM Davies A Karnad A Samaniego F Spira AI Fields PA Menne T Boni J Cruz H Feingold J He S Wuerthner J Hamadani M Adct-301 (Camidanlumab Tesirine), a novel pyrrolobenzodiaze-based CD25-targeting antibody drug conjugate, in a phase 1 study of replased/refractory non-Hodgkin lymphoma shows activity in T-cell lymphoma Blood 2018 132 1658

117. Stathis A Flinn IW Madan S Maddocks K Freedman A Weitman S Zucca E Munteanu MC Lia Palomba M Safety, tolerability, and preliminary activity of IMGN529, a CD37-targeted antibody-drug conjugate, in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: a dose-escalation, phase I study Invest New Drugs 2018 36 5 869 876 10.1007/s10637-018-0570-4 29453628 PMC6153548

118. Sawas A Savage KJ Perez R Advani RH Butturini A Lackey J Trave F Anand B Huang Y Reyno L O'Connor OA A phase 1 study of the anti-CD37 Antibody-drug conjugate AGS67E in advanced lymphoid malignancies Interim results. Blood 2015 126 23 3976

119. Coiffier B Thieblemont C de Guibert S Dupuis J Ribrag V Bouabdallah R Morschhauser F Navarro R Le Gouill S Haioun C Houot R Casasnovas O Holte H Lamy T Broussais F Payrard S Hatteville L Tilly H A phase II, single-arm, multicentre study of coltuximab ravtansine (SAR3419) and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma Br J Haematol 2016 173 5 722 730 10.1111/bjh.13992 27010483

120. Kantarjian HM Lioure B Kim SK Atallah E Leguay T Kelly K Marolleau JP Escoffre-Barbe M Thomas XG Cortes J Jabbour E O'Brien S Bories P Oprea C Hatteville L Dombret H A phase II study of coltuximab ravtansine (SAR3419) monotherapy in patients with relapsed or refractory acute lymphoblastic leukemia Clin Lymphoma Myeloma Leuk 2016 16 3 139 145 10.1016/j.clml.2015.12.004 26775883 PMC5557033

121. Li D. Poon K. A. Yu S.-F. Dere R. Go M. Lau J. Zheng B. Elkins K. Danilenko D. Kozak K. R. Chan P. Chuh J. Shi X. Nazzal D. Fuh F. McBride J. Ramakrishnan V. de Tute R. Rawstron A. Jack A. S. Deng R. Chu Y.-W. Dornan D. Williams M. Ho W. Ebens A. Prabhu S. Polson A. G. DCDT2980S, an Anti-CD22-Monomethyl Auristatin E Antibody-Drug Conjugate, Is a Potential Treatment for Non-Hodgkin Lymphoma Molecular Cancer Therapeutics 2013 12 7 1255 1265 10.1158/1535-7163.MCT-12-1173 23598530

122. Advani RH Lebovic D Chen A Brunvand M Goy A Chang JE Hochberg E Yalamanchili S Kahn R Lu D Agarwal P Dere RC Hsieh HJ Jones S Chu YW Cheson BD Phase I study of the anti-CD22 antibody-drug conjugate pinatuzumab vedotin with/without rituximab in patients with relapsed/refractory B-cell non-Hodgkin lymphoma Clin Cancer Res 2017 23 5 1167 1176 10.1158/1078-0432.CCR-16-0772 27601593 PMC6035878

123. Kuhn DJ Dou QP The role of interleukin-2 receptor alpha in cancer Front Biosci 2005 10 1462 1474 10.2741/1631 15769637

124. Goldberg AD Tallman MS Solh MM Ungar D Rizzieri DA Walter RB Spira AI Chung KY Stock W He S Boni J Atallah E Results from an ongoing phase 1 study indicate ACDT-301 (Camidanlumab Tesirine) is well-tolerated in patients with relapsed or refractory CD25-positive acute leukemia Blood 2017 130 2662

125. Lapalombella R Yeh YY Wang L Ramanunni A Rafiq S Jha S Staubli J Lucas DM Mani R Herman SE Johnson AJ Lozanski A Andritsos L Jones J Flynn JM Lannutti B Thompson P Algate P Stromatt S Jarjoura D Mo X Wang D Chen CS Lozanski G Heerema NA Tridandapani S Freitas MA Muthusamy N Byrd JC Tetraspanin CD37 directly mediates transduction of survival and apoptotic signals Cancer Cell 2012 21 5 694 708 10.1016/j.ccr.2012.03.040 22624718 PMC3360882

126. Zhao X Lapalombella R Joshi T Cheney C Gowda A Hayden-Ledbetter MS Baum PR Lin TS Jarjoura D Lehman A Kussewitt D Lee RJ Caligiuri MA Tridandapani S Muthusamy N Byrd JC Targeting CD37-positive lymphoid malignancies with a novel engineered small modular immunopharmaceutical Blood 2007 110 7 2569 2577 10.1182/blood-2006-12-062927 17440052 PMC1988922

127. Deckert J Park PU Chicklas S Yi Y Li M Lai KC Mayo MF Carrigan CN Erickson HK Pinkas J Lutz RJ Chittenden T Lambert JM A novel anti-CD37 antibody-drug conjugate with multiple anti-tumor mechanisms for the treatment of B-cell malignancies Blood 2013 122 20 3500 3510 10.1182/blood-2013-05-505685 24002446

128. Hicks SW Lai KC Gavrilescu LC Yi Y Sikka S Shah P Kelly ME Lee J Lanieri L Ponte JF Sloss CM Romanelli A The antitumor activity of IMGN529, a CD37-targeting antibody-drug conjugate, is potentiated by rituximab in non-Hodgkin lymphoma models Neoplasia 2017 19 9 661 671 10.1016/j.neo.2017.06.001 28753442 PMC5540712

129. Pereira DS Guevara CI Jin L Mbong N Verlinsky A Hsu SJ Avina H Karki S Abad JD Yang P Moon SJ Malik F Choi MY An Z Morrison K Challita-Eid PM Donate F Joseph IB Kipps TJ Dick JE Stover DR AGS67E, an Anti-CD37 Monomethyl Auristatin E Antibody-drug conjugate as a potential therapeutic for B/T-cell malignancies and AML: a new role for CD37 in AML Mol Cancer Ther 2015 14 7 1650 1660 10.1158/1535-7163.MCT-15-0067 25934707 PMC4557793

130. Borst J Hendriks J Xiao Y CD27 and CD70 in T cell and B cell activation Curr Opin Immunol 2005 17 3 275 281 10.1016/j.coi.2005.04.004 15886117

131. Phillips T Barr PM Park SI Kolibaba K Caimi PF Chhabra S Kingsley EC Boyd T Chen R Carret AS Gartner EM Li H Yu C Smith DC A phase 1 trial of SGN-CD70A in patients with CD70-positive diffuse large B cell lymphoma and mantle cell lymphoma Invest New Drugs 2019 37 2 297 306 10.1007/s10637-018-0655-0 30132271 PMC6440937

132. Owonikoko TK Hussain A Stadler WM Smith DC Kluger H Molina AM Gulati P Shah A Ahlers CM Cardarelli PM Cohen LJ First-in-human multicenter phase I study of BMS-936561 (MDX-1203), an antibody-drug conjugate targeting CD70 Cancer Chemother Pharmacol 2016 77 1 155 162 10.1007/s00280-015-2909-2 26576779

133. Tannir NM Forero-Torres A Ramchandren R Pal SK Ansell SM Infante JR de Vos S Hamlin PA Kim SK Whiting NC Gartner EM Zhao B Thompson JA Phase I dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma Invest New Drugs 2014 32 6 1246 1257 10.1007/s10637-014-0151-0 25142258

134. Ishitsuka K Jimi S Goldmacher VS Ab O Tamura K Targeting CD56 by the maytansinoid immunoconjugate IMGN901 (huN901-DM1): a potential therapeutic modality implication against natural killer/T cell malignancy Br J Haematol 2008 141 1 129 131 10.1111/j.1365-2141.2008.07000.x 18279455

135. Skaletskaya A Setiady YY Park PU Lutz RJ Lorvotuzumab mertansine (IMGN901) immune effector activity and its effect on human NK cells Cancer Research 2011 71 Suppl 8 770

136. Ailawadhi S Kelly KR Vescio RA Jagannath S Wolf J Gharibo M Sher T Bojanini L Kirby M Chanan-Khan A A phase I study to assess the safety and pharmacokinetics of single-agent lorvotuzumab mertansine (IMGN901) in patients with relapsed and/or refractory CD-56-positive multiple myeloma Clin Lymphoma Myeloma Leuk 2019 19 1 29 34 10.1016/j.clml.2018.08.018 30340993 PMC9059793

137. Govindan SV Cardillo TM Sharkey RM Tat F Gold DV Goldenberg DM Milatuzumab-SN-38 Conjugates for the Treatment of CD74 Cancers Molecular Cancer Therapeutics 2013 12 6 968 978 10.1158/1535-7163.MCT-12-1170 23427296

138. Jagannath S Heffner LT Jr Ailawadhi S Munshi NC Zimmerman TM Rosenblatt J Lonial S Chanan-Khan A Ruehle M Rharbaoui F Haeder T Wartenberg-Demand A Anderson KC Indatuximab ravtansine (BT062) monotherapy in patients with relapsed and/or refractory multiple myeloma Clin Lymphoma Myeloma Leuk 2019 19 6 372 380 10.1016/j.clml.2019.02.006 30930134

139. Trudel S Lendvai N Popat R Voorhees PM Reeves B Libby EN Richardson PG Hoos A Gupta I Bragulat V He Z Opalinska JB Cohen AD Antibody-drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an update on safety and efficacy from dose expansion phase I study Blood Cancer Journal 2019 9 37 10.1038/s41408-019-0196-6 30894515 PMC6426965

140. Berdeja JG Hernandez-Ilizaliturri F Chanan-Khan A Patel M Kelly KR Running KL Murphy M Guild R Carrigan C Ladd S Wolf BB O'Leary JJ Ailawadhi S Phase I study of lorvotuzumab mertansine (LM, IMGN901) in combination with lenalidomide (Len) and dexamethasone (Dex) in patients with CD56-positive relapsed or relapsed/refractory multiple myeloma (MM) Blood 2012 120 21 728

141. Stein R. Mattes M. J. Cardillo T. M. Hansen H. J. Chang C.-H. Burton J. Govindan S. Goldenberg D. M. CD74: A New Candidate Target for the Immunotherapy of B-Cell Neoplasms Clinical Cancer Research 2007 13 18 5556s 5563s 10.1158/1078-0432.CCR-07-1167 17875789

142. Kaufman JL Niesvizky R Stadtmauer EA Chanan-Khan A Siegel D Horne H Wegener WA Goldenberg DM Phase I, multicentre, dose-escalation trial of monotherapy with milatuzumab (humanized anti-CD74 monoclonal antibody) in relapsed or refractory multiple myeloma Br J Haematol 2013 163 4 478 486 10.1111/bjh.12565 24112026

143. Sanderson RD Lalor P Bernfield M Lymphocytes-B Express and Lose Syndecan at Specific Stages of Differentiation Cell Regulation 1989 1 1 27 35 10.1091/mbc.1.1.27 2519615 PMC361422

144. Schonfeld K Zuber C Pinkas J Hader T Bernoster K Uherek C Indatuximab ravtansine (BT062) combination treatment in multiple myeloma: pre-clinical studies Journal of Hematology & Oncology 2017 10 13 10.1186/s13045-016-0380-0 28077160 PMC5225632

145. Kelly KR Siegel DS Chanan-Khan AA Somlo G Heffner LT Jagannath S Zimmerman T Munshi NC Madan S Mohrbacher A Lonial S Barmaki-Rad F Ruhle M Herrmann E Wartenberg-Demand A Haeder T Anderson KC Indatuximab ravtansine (BT062) in combination with low-dose dexamethasone and lenalidomide or pomalidomide: clinical activity in patients with relapsed / refractory multiple myeloma Blood 2016 128 22 4486

146. Sanchez E Li MJ Kitto A Li J Wang CS Kirk DT Yellin O Nichols CM Dreyer MP Ahles CP Robinson A Madden E Waterman GN Swift RA Bonavida B Boccia R Vescio RA Crowley J Chen HM Berenson JR Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival British Journal of Haematology 2012 158 6 727 738 10.1111/j.1365-2141.2012.09241.x 22804669

147. Lee L Bounds D Paterson J Herledan G Sully K Seestaller-Wehr LM Fieles WE Tunstead J McCahon L Germaschewski FM Mayes PA Craigen JL Rodriguez-Justo M Yong KL Evaluation of B cell maturation antigen as a target for antibody drug conjugate mediated cytotoxicity in multiple myeloma British Journal of Haematology 2016 174 6 911 922 10.1111/bjh.14145 27313079

148. Tai YT Mayes PA Acharya C Zhong MY Cea M Cagnetta A Craigen J Yates J Gliddon L Fieles W Hoang B Tunstead J Christie AL Kung AL Richardson P Munshi NC Anderson KC Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma Blood 2014 123 20 3128 3138 10.1182/blood-2013-10-535088 24569262 PMC4023420

149. Zhang C Liu J Zhong JF Zhang X Engineering CAR-T cells Biomarker Research 2017 5 1 22 10.1186/s40364-017-0102-y 28652918 PMC5482931

150. Wei G Ding L Wang J Hu Y Huang H Advances of CD19-directed chimeric antigen receptor-modified T cells in refractory/relapsed acute lymphoblastic leukemia Experimental Hematology & Oncology 2017 6 1 10 10.1186/s40164-017-0070-9 28413717 PMC5391552

151. Yu S Liu Q Han X Qin S Zhao W Li A Wu K Development and clinical application of anti-HER2 monoclonal and bispecific antibodies for cancer treatment Experimental Hematology & Oncology 2017 6 1 31 10.1186/s40164-017-0091-4 29209558 PMC5704598

152. Porter DL Levine BL Kalos M Bagg A June CH Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia N Engl J Med 2011 365 8 725 733 10.1056/NEJMoa1103849 21830940 PMC3387277

153. Wang J Hu Y Huang H Current development of chimeric antigen receptor T-cell therapy Stem Cell Investigation 2018 5 44 10.21037/sci.2018.11.05 30701179 PMC6327156

154. Maude SL Laetsch TW Buechner J Rives S Boyer M Bittencourt H Bader P Verneris MR Stefanski HE Myers GD Qayed M De Moerloose B Hiramatsu H Schlis K Davis KL Martin PL Nemecek ER Yanik GA Peters C Baruchel A Boissel N Mechinaud F Balduzzi A Krueger J June CH Levine BL Wood P Taran T Leung M Mueller KT Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia N Engl J Med 2018 378 5 439 448 10.1056/NEJMoa1709866 29385370 PMC5996391

155. Neelapu SS Locke FL Bartlett NL Lekakis LJ Miklos DB Jacobson CA Braunschweig I Oluwole OO Siddiqi T Lin Y Timmerman JM Stiff PJ Friedberg JW Flinn IW Goy A Hill BT Smith MR Deol A Farooq U McSweeney P Munoz J Avivi I Castro JE Westin JR Chavez JC Ghobadi A Komanduri KV Levy R Jacobsen ED Witzig TE Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma N Engl J Med 2017 377 26 2531 2544 10.1056/NEJMoa1707447 29226797 PMC5882485