Trial watch: Monoclonal antibodies in cancer therapy.

Introduction

In 1975, Georges Köhler and César Milstein described for the first time an experimental setup allowing for the cost-effective production of high quantities of antibodies exhibiting the same antigenic specificity. 1 This breakthrough discovery, which allowed Köhler and Milstein to win the 2004 Nobel Prize for Medicine or Physiology, de facto revolutionized an unbelievable number of research protocols and clinical applications. 2 During the past 30 years, the hybridoma technology originally described by Köhler and Milstein (which was purely murine and hence associated with relevant immunogenicity issues) has been consistently ameliorated, resulting in the production of ever more refined reagents for clinical applications. 3 In 1986, the US Food and Drud Administration (FDA) approved muromonab, a murine IgG1 specific for CD3, for the therapy of transplanted patients undergoing rejection. 4 Since then, dozens of monoclonal antibodies (mAbs), including murine, chimeric as well humanized reagents, have been approved by international regulatory agencies (including FDA and the European Medicines Agency, EMA) for use in humans against multiple diseases, including (but not limited to) autoimmune disorders and cancer. 2 , 5 Of these, no less than 14 mAbs, including naked reagents as well as mAbs coupled to antibiotics or radioactive isotopes, are nowadays authorized for use in cancer patients ( Table 1 ). 5 , 6

One year ago, concomitant with the launch of OncoImmunology , we published the first Trial Watch of what has then become a monthly series, 6 - 14 dealing with the use of mAbs in cancer therapy. 6 As described in details therein, mAbs that potentially exert antineoplastic effects belong to one of six, non-mutually exclusive classes: (1) mAbs that target cancer cell-intrinsic pro-survival signal transduction cascades (e.g., cetuximab, which inhibits the epidermal growth factor receptor, EGFR, and is currently employed for the therapy of colorectal cancer); 15 (2) mAbs that interrupt the trophic interaction between malignant cells and their stroma, hence indirectly inhibiting tumor growth (e.g., bevacizumab, which targets the vascular endothelial growth factor, VEGF, and is currently approved for use in patients affected by breast, lung, renal and colorectal carcinoma); 16 (3) mAbs that recognize antigens expressed on the surface of tumor cells and exert antineoplastic effects by engaging immune effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), 5 , 17 , 18 antibody-dependent cellular phagocytosis (ADCP), 19 and complement-dependent cytotoxicity (CDC) 20 , 21 (e.g., rituximab, a naked anti-CD20 currently approved for use in lymphoma patients); 22 - 24 (4) trifunctional (bispecific) mAbs, which can bind two distinct antigenic targets while retaining the ability of activating immune effector functions (e.g., catumaxomab, an anti-CD3, anti-EpCAM chimeric mAb nowadays is use for the therapy of malignant ascites in patient with EpCAM + neoplasms); 25 (5) immunoconjugates (e.g., 90 Y-ibritumomab tiuxetan and 131 I-tositumomab, two radionuclide-coupled anti-CD20 mAbs that are currently approved for the treatment of lymphoma patients); 26 , 27 and (6) immunostimulatory mAbs, i.e., mAbs that facilitate the development of an antitumor immune response by influencing the balance between the immunogenicity of malignant cells and the immunosuppressive mechanisms that they normally establish (e.g., ipilimumab, an anti-CTLA-4 mAb nowadays employed in melanoma patients). 28 - 31

Here, we will summarize the latest developments in the clinical development of mAbs for cancer therapy, focusing on high impact studies that have been published during the last 15 months and clinical trials that have been launched in the same period to investigate the therapeutic profile of promising, yet hitherto experimental, mAbs. Of note, in this period, FDA has authorized one novel mAb for use in cancer patients and one oncological indication for a mAb that had previously been approved for the therapy of non-oncological patients (source http://www.cancer.gov/cancertopics/druginfo ). Thus, brentuximab vedotin, an anti-CD30 monomethyl auristatin E (MMAE) conjugate, is now approved for the treatment of relapsed Hodgkin lymphoma and relapsed systemic anaplastic large cell lymphoma patients, 32 , 33 In addition, denosumab, a receptor activator of NFκB ligand (RANKL)-targeting mAb that was employed in postmenopausal women at risk for osteoporosis, can nowadays be used to increase bone mass in patients who are at high risk of fracture as they undergo androgen deprivation therapy for non-metastatic prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer. 34 Finally, the approval status of rituximab and cetuximab has recently been expanded in terms of therapeutic schedules and therapy-eligible patients subsets, respectively, while the authorization of bevacizumab as a therapeutic option for breast cancer patients has been revoked ( Table 1 ).

Update on Clinical Reports

Since the submission of our previous Trial Watch on this topic (August 2011), 6 high-impact journals have published the results of no less than 50 clinical studies investigating the safety and efficacy of mAbs for cancer therapy. Obviously, a majority of these studies involved FDA-approved mAbs ( Table 1 ), including bevacizumab (16 studies), 35 - 50 trastuzumab (11 studies), 46 , 51 - 60 rituximab (10 studies), 61 - 70 cetuximab (8 studies), 71 - 78 ipilimumab (4 studies), 79 - 82 alemtuzumab (2 studies), 83 , 84 and denosumab (1 study). 85 In addition, a few high-impact publications have reported on the clinical profile of experimental mAbs, including immunostimulatory anti-PD-1 and anti-PD-L1 mAbs, 86 , 87 the anti-CD22 calecheamicin conjugate inotuzumab ozogamicin, 88 the anti-CD19 maytansinoid conjugate SAR3419, 89 cixutumumab and figitumumab, two distinct mAbs specific for insulin-like growth factor 1 receptor (IGF1R), 90 , 91 pertuzumab, an anti-HER2 mAb, 92 , 93 and the CS1-targeting mAb elotuzumab. 94 , 95

Thus, the clinical potential of FDA-approved mAbs, most often combined with conventional chemotherapeutic approaches, is under intensive investigation, an effort that will presumably lead to the approval of further oncological indications for these agents in the near future. In this respect, bevacizumab has been found to prolong progression-free survival (PFS) and overall survival (OS) in ovarian cancer patients treated with carboplatin and paclitaxel, in two randomized Phase III studies, 41 , 42 and to improve the rate of pathological complete responses (pCRs) among HER2-negative breast carcinoma patients undergoing neoadjuvant docetaxel-based chemotherapy, again in two large randomized Phase III trials. 44 , 45 The clinical profile of trastuzumab has most often been evaluated in cohorts of breast cancer patients, 46 , 51 - 58 , 60 reflecting the indications for which it has been authorized by FDA. In particular, two distinct, randomized Phase III studies demonstrated that the combination of neoadjuvant chemotherapy, trastuzumab and a chemical inhibitor of HER2, lapatinib, is clinically superior to use of either approach alone. 58 , 60 Similar to trastuzumab, rituximab has most extensively been tested in clinical settings that match its FDA-approved indications, i.e., cohorts of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) patients. 61 - 67 One notable exception to this trend is represented by the study of Kluin-Nelemans et al., demonstrating that rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone is efficient in old patients affected by mantle-cell lymphoma. 70 Cetuximab has been tested in a few different clinical settings, including cohorts of non-small cell lung carcinoma (NSCLC), pancreatic cancer and colorectal carcinoma patients. 71 - 78 Notably, EGFR expression levels have been shown to predict a survival benefit from the addition of cetuximab to first-line conventional chemotherapy in NSCLC patients. 74 Ipilimumab has been tested in cohorts of melanoma and NSCLC patients, alone or combined with paclitaxel and cisplatin, respectively, 81 , 82 as well as in prostate cancer patients undergoing vaccination, 79 , 80 invariably providing clinical benefits, at least to some extent. Finally, alemtuzumab and denosumab have been shown to improve the therapeutic potential of fludarabine in a cohort of CLL patients, 83 and to reduce the incidence of bone metastases in subjects affected by castration-resistant prostate carcinoma. 85

Some experimental mAbs have also generated remarkable clinical results during the last 15 months. For instance, the mAb-mediated blockade of the interaction between the inhibitory receptor PD-1 (which is expressed by T cells) and its ligand (PD-L1), undertaken as a standalone intervention with either anti-PD-1 (MDX-1106, BMS-936558) or anti-PD-L1 (MDX-1105, BMS-936559) mAbs, has been shown to induce tumor regression or disease stabilization in a relatively small (but encouraging) proportion of patients affected by NSCLC, melanoma and renal cell carcinoma (RCC). 86 , 87 Inotuzumab ozogamicin has been associated with a promising therapeutic profile among refractory and relapsed acute lymphocytic leukemia patients. 88 The intravenous administration of SAR3419 to relapsed CD19 + B-cell lymphoma patients has been found to be safe and to elicit a consistent rate of clinical responses. 89 Along similar lines, anti-IGF1R mAbs such as cixutumumab and figitumumab have been shown to be well tolerated by children affected by refractory Ewing sarcoma, exhibiting modest antineoplastic activity as single agents. 90 , 91 The inclusion of pertuzumab in combinatorial regimens involving trastuzumab (alone or combined with docetaxel-based chemotherapy) have been associated with improved PFS (compared with the use of either mAb alone or chemotherapy plus trastuzumab only), in cohorts of HER2 + breast cancer patients. 92 , 93 Finally, in two distinct Phase I clinical trials, the combination of elotuzumab and bortezomib or lenalidomide plus low-dose dexamethasone was well tolerated and exhibited a promising efficacy in patients affected by relapsed or refractory multiple myeloma. 94 , 95

Focusing on recent, high-impact mAb-related translational research, we have found of particular interest the studies by Yonesaka et al., Diaz et al. and Misale et al., demonstrating that colorectal carcinoma patients become refractory to EGFR-targeting mAbs including cetuximab and panitumumab along with the emergence of KRAS mutations or with an increased signaling via the EGFR-related receptor HER2; 96 , 97 as well as the work by Prahallad et al., revealing that—at least in a fraction of cases—the unresponsiveness of colon carcinoma patients to BRAF V600E inhibitors stems from a feedback hyperactivation of EGFR signaling. 98

Update on Investigational Monoclonal Antibodies under Clinical Evaluation

When this Trial Watch was being redacted (October 2012), official sources listed 45 clinical trials launched after 2011, August 1 that would investigate the safety and therapeutic profile of hitherto investigational mAbs in cancer patients (source www.clinicaltrials.gov ).

Bavituximab is a chimeric IgG1 specific for phosphatidylserine (PS), an anionic phospholipid that—under physiological conditions—is found in the inner leaflet of the plasma membrane. 99 PS translocates to the cell surface in some instances of cell death, 100 - 102 cell activation and malignant transformation, and has been proposed to constitute a tumor vasculature-specific marker. 103 , 104 Encouraging preclinical findings by Ran et al. 99 supported the evaluation of bavituximab in clinical settings. Recent results from a Phase I study indicate that bavituximab at doses up to 3 mg/Kg/week is well tolerated by patients with advanced solid tumors. 105 Recently (since 2011, August 1), one single Phase I trial has been launched to assess the tolerability and preliminary therapeutic profile of bavituximab, combined with capecitabine and radiotherapy, in rectal adenocarcinoma patients ( NCT01634685 ) ( Table 2 ).

BC8 , a CD45-targeting mAb that most often is conjugated to radionuclides (e.g., 131 I, 111 In), is currently under preclinical and clinical investigation for the treatment of CD45-expressing hematological malignancies. 106 The combination of BC8 with cyclophosphamide and total body irradiation (TBI) has previously been shown to be tolerated and convey clinical benefits in a small cohort of patients affected by myelodysplastic syndrome (MDS) and acute lymphoid leukemia (ALL). 107 Recently (since 2011, August 1), two Phase I trials have been launched to test the clinical profile of BC8, one involving multiple myeloma patients treated with BC8 in combination with fludarabine and TBI ( NCT01503242 ), and one involving patients with refractory or relapsed lymphoid malignancies receiving BC8 as a standalone intervention ( NCT01678443 ), in both cases as a pre-transplantation conditioning regimen ( Table 2 ).

Blinatumomab belongs to the category of so-called BiTEs (bispecific T-cell engagers), i.e., bi-specific mAbs that invariably target CD3 (a component of the TCR signal transduction machinery expressed by T cells) and a tumor-associated antigen (in this case, CD19, a transmembrane protein mainly expressed by B cells). 108 Hence, unlike conventional monospecific mAbs, blinatumomab exerts antineoplastic effects by physically bridging malignant B cells and host T cells, hence promoting the cytotoxic activity of the latter. 108 High response rates and durable remissions have been observed in the first clinical trials testing the safety and therapeutic profile of blinatumomab among B-cell NHL and B-precursor ALL patients. 109 - 111 Recently (since 2011, August 1), two Phase I/II trials have been initiated to investigate the safety and efficacy of blinatumomab, given as a standalone intervention, in subjects affected by B-precursor ALL ( NCT01466179 , NCT01471782 ) ( Table 2 ).

Ch14.18 is a chimeric IgG1 specific for GD2, a disialoganglioside GD2 that is often abundant at the surface neuroendocrine tumor cells. 112 , 113 The evaluation of the safety and efficacy of Ch14.18 as a standalone agent for the treatment of melanoma and neuroblastoma has begun in the early 1990s, 114 , 115 with relatively unsatisfactory results. Later on, a few clinical studies have investigated the clinical potential of combinatorial regimens consisting of Ch14.18 in association with immunostimulatory cytokines like interleukin (IL)-2 and granulocyte macrophage-colony stimulating factor (GM-CSF) or metronomic chemotherapy, 116 - 119 reporting rather promising findings, in particular for the use of Ch14.18 in association with GM-CSF, IL-1 and isotretinoin (a retinoid) in high-risk neuroblastoma patients. 118 Recently (since 2011, August 1), two Phase I/II trials have been launched to test the therapeutic potential of Ch14.18, alone or combined with GM-CSF, IL-1 and isotretinoin, in neuroblastoma patients ( NCT01418495 ; NCT01592045 ) ( Table 2 ).

Cixutumumab (a fully human IgG1), dalotuzumab (a humanized IgG1) and ganitumab (a fully human IgG1) all target IGFR1, a transmembrane receptor that is overexpressed or hyperactivated by most, if not all, malignant tissues, hence operating as an anti-apoptotic signal transducer. 120 According to the results of early clinical trials, cixutumumab and dalotuzumab as single agents as well as the combination of cixutumumab and temsirolimus (an inhibitor of the intracellular signaling pathway elicited by IGFR1) are generally well tolerated by patients bearing advanced solid tumors, 91 , 121 - 123 with prominent adverse effects involving the dermis. 124 Conversely, dose-limiting toxicities have been reported to develop among unselected NSCLC patients treated with cixutumumab in combination with the EGFR inhibitor erlotinib at full dosage. 125 In 2012, results from 4 distinct clinical studies testing the safety and efficacy of ganitumab in patients affected by Ewing family tumors, pancreatic carcinoma or other solid malignancies have been published. 126 - 129 Globally, ganitumab—both as a single agent and associated with targeted agents or conventional chemotherapy—appears to be well tolerated and to exert antineoplastic activity, at least in a fraction of patients. 126 - 129 This said, results from less recent Phase III studies have shown that targeting the IGF1R pathway is not associated with clear clinical benefits in cancer patients. 130 Accordingly, several anti-IGF1R programs—including one large randomized Phase III study that originally aimed at testing the therapeutic potential of ganitumab among prostatic cancer patients ( NCT01231347 )—have lately been discontinued. 130 , 131 Recently (since 2011, August 1), two Phase II clinical trials have been launched to test the clinical profile of cixutumumab, either as a standalone intervention or combined with temsirolimus, in melanoma, sarcoma and brain cancer patients ( NCT01413191 ; NCT01614795 ). In addition, three Phase I/II studies have been initiated to investigate the safety and efficacy of dalotuzumab, alone or in combination with ridaforolimus (a functional analog of temsirolimus) or conventional chemotherapeutics, in subjects bearing breast carcinoma, colorectal carcinoma or advanced solid tumors ( NCT01431547 ; NCT01605396 ; NCT01609231 ). Finally, four Phase I/II studies have been initiated to assess the therapeutic potential of ganitumab, in combination with conventional chemotherapy, radiotherapy or trastuzumab, in individuals affected by breast carcinoma, pancreatic carcinoma or other advanced solid neoplasms ( NCT01298401 ; NCT01473303 ; NCT01479179 ; NCT01562899 ). Of note, one of these studies ( NCT01473303 ) is listed as complete, though results are not available, while another one ( NCT01479179 ) has been withdrawn prior to patient enrollment, which somehow reflects current feelings about mAb-based anti-IGF1R cancer therapy ( Table 2 ).

MDX-1106 is a fully human IgG4 that specifically binds PD-1, a transmembrane receptor that—upon binding by its cognate ligand PD-L1, generates immunosuppressive signals in activated T cells. 132 - 134 In 2012, MDX-1106 (as well as of the PD-L1-targeting antibody MDX-1105 ) has been shown to be well tolerated and to induce objective clinical responses in a relatively small (but encouraging) proportion of patients affected by advanced NSCLC, melanoma and RCC. 86 , 87 Recently (since 2011, August 1), no less than 10 Phase I-III clinical trials have been launched to investigate the clinical potential of MDX-1105 and MDX-1106, given as standalone agents or combined with conventional chemotherapy (e.g., carboplatin + paclitaxel or cisplatin + gemcitabine or cisplatin + paclitaxel), targeted therapy (e.g., pazopanib or sunitinib, two tyrosine kinase receptor inhibitors) or immunostimulatory agents (e.g., recombinant IL-21), in cohorts of patients affected by hematological tumors ( NCT01452334 ; NCT01592370 ), melanoma ( NCT01621490 ), NSCLC ( NCT01454102 ; NCT01642004 ; NCT01673867 ), hepatocellular carcinoma ( NCT01658878 ), RCC ( NCT01472081 ; NCT01668784 ), and advanced solid tumors ( NCT01629758 ) ( Table 2 ). Of note, the only study involving MDX-1105 ( NCT01452334 ) has been withdrawn prior to patient enrollment, for undeclared reasons (source www.clinicaltrials.gov ).

Both necitumumab (a fully human IgG1) and nimotuzumab (a humanized IgG1) specifically bind EGFR, a transmembrane receptor with tyrosine kinase activity that is hyperactivated, due to point mutations, in a number of solid malignancies. Accordingly, a number of EGFR-targeting therapeutics have already been approved by FDA and other regulatory agencies for use in cancer patients, including the cell-permeant tyrosine kinase inhibitors erlotinib and gefinitib 135 - 137 and the anti-EGFR mAbs cetuximab and panitumumab ( Table 1 ). 138 , 139 Still, the clinical interest in EGFR-targeting approaches is not decreasing, at least in part owing to the fact that most, if not all, FDA approved EGFR-targeting agents have been associated with the development of chemoresistance in a consistent fraction of patients. 96 - 98 , 140 The clinical development of nimotuzumab appears to be more advanced than that of necitumumab. Indeed, during the last 15 months, several pilot or Phase I studies investigating the safety and preliminary therapeutic profile of nimotuzumab (given as a standalone intervention or combined with standard radio- or chemotherapeutic regimens) in patients affected by various solid malignancies have been concluded, overall reporting a low incidence of tolerable adverse effects and improved disease outcome, at least in a fraction of cases. 141 - 154 Conversely, no reports have been published since 2010 on the clinical profile of necitumumab. 144 Recently (since 2011, August 1), a total of 9 Phase II clinical trials have been initiated to investigate the safety and efficacy of necitumumab ( NCT01606748 ; NCT01624467 ) or nimotuzumab ( NCT01425736 ; NCT01463605 ; NCT01486992 ; NCT01498562 ; NCT01516996 ; NCT01616849 ; NCT01688700 ), as single agents or associated with standard chemotherapy, in cohorts of head and neck cancer ( NCT01425736 , NCT01516996 ; NCT01616849 ) esophageal cancer ( NCT01463605 ; NCT01486992 ; NCT01688700 ) and NSCLC ( NCT01498562 ) patients, as well as of individuals affected by various solid tumors ( NCT01606748 ; NCT01624467 ) ( Table 2 ).

Ramucirumab (IMC-1121B) is a fully human IgG1 specific for the VEGF receptor 2 (VEGFR2). By antagonizing endogenous VEGF signaling, 155 ramucirumab inhibits of the most prominent interactions between neoplastic and stromal cells, i.e., neo-angiogenesis. 156 Early Phase I clinical trials demonstrated that ramucirumab is generally well tolerated by cancer patients, 155 , 157 and prompted the launch of a randomized, double-blind Phase III study to evaluate whether ramucirumab can improve the efficacy of docetaxel-based chemotherapy in subjects bearing stage IV NSCLC ( NCT01168973 , registered at www.clinicaltrials.gov on July 2010). 158 This study has not yet been concluded. More recently (since 2011, August 1), 5 distinct Phase I clinical trials have been commenced to investigate the tolerability and efficacy of ramucirumab, most often combined with conventional chemotherapeutics, in subjects affected by breast carcinoma ( NCT01427933 ) or other solid neoplasms ( NCT01515306 ; NCT01567163 ; NCT01634555 ; NCT01682135 ) ( Table 2 ).

Siltuximab (CNTO-328) is a chimeric IgG1 that binds to IL-6, a pleiotropic cytokine that reportedly modulates several aspects of oncogenesis and tumor progression, including the balance between cell proliferation and cell death as well as neo-angiogenesis. 159 Siltuximab-based monotherapy as well as combinatorial regimens including siltuximab and mitoxantrone + prednisone or siltuximab + docetaxel have lately been reported to be well tolerated by prostate cancer patients, although objective effects on disease outcome could not always be documented. 160 - 162 Since 2011, August 1, 3 Phase I/II clinical trials have been launched to assess the therapeutic profile of siltuximab, as a single agent or combined with best supportive care or bortezomib + dexamethasone + lenalidomide, in MDS ( NCT01513317 ) and multiple myeloma ( NCT01484275 ; NCT01531998 ) patients ( Table 2 ). Conversely, the Phase III trial NCT01266811 , which was initiated in December 2010 to test the efficacy of siltuximab + bortezomib + dexamethasone in similar patient cohorts has been withdrawn prior to patient enrollment for undeclared reasons (source www.clinicaltrials.gov ).

Tigatuzumab (CS-1008) is a humanized IgG1 that functions as an agonist for tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAILR2), hence promoting the death of TRAILR2-expressing malignant (but not non-transformed) cells. 163 Although the molecular basis underlying the selectivity of tigatuzumab remains unclear, 164 , 165 the results of preliminary Phase I-II studies in cancer patients were encouraging, suggesting that tigatuzumab is generally well tolerated. 166 Recently (since 2011, August 1), 1 Phase II clinical trial has been initiated to test the safety and efficacy of tigatuzumab combined with abraxane (protein-bound paclitaxel particles), in breast carcinoma patients ( NCT01307891 ) ( Table 2 ).

Tremelimumab (ticilimumab, CP-675,206) is a human IgG2 that, similar to the FDA-approved mAb ipilimumab, inhibits the development of peripheral tolerance by antagonizing the immunosuppressive receptor CTLA-4 on the surface of T cells. 167 , 168 Combinatorial regimens including tremelimumab + high-dose interferon α-2b (IFNα-2b) and tremelimumab + androgen deprivation have recently been shown to be well tolerated by melanoma and prostate carcinoma patients, 169 , 170 respectively. Since 2011, August 1, 2 Phase II studies have been launched to investigate the clinical profile of tremelimumab, invariably employed as a standalone intervention, in mesothelioma patients ( NCT01649024 ; NCT01655888 ) ( Table 2 ).

Concluding Remarks

In no more than 15 months, besides extending the indications of mAbs that were previously approved in oncological settings, the US FSA has authorized the use in cancer patients of two novel mAbs, brentuximab vedotin and denosumab. 32 - 34 In the very same period, (1) results from no less than 50 clinical studies testing the safety and antineoplastic profile of mAbs have been published in top-impact forums; and (2) approximately 50 novel mAb-based clinical trials enrolling cohorts of cancer patients have been registered at www.clinicaltrials.gov . Thus, the interest in the clinical development of mAbs for cancer therapy remains very high.

With two notable exceptions (i.e., NCT01266811 and NCT01231347 ), all Phase III studies that we listed in our latest Trial Watch dealing with mAbs and cancer therapy are still ongoing. 6 The results of these large, randomized clinical trials are likely to determine whether novel mAbs will soon be authorized by FDA and/or other international regulatory agencies for use in cancer patients. In addition, an intense wave of preclinical investigation is ongoing not only to discover novel mAb-druggable oncology-relevant targets, but also to generate further insights into the molecular and cellular circuitries whereby mAbs actually exert antineoplastic effects and how this knowledge can be translated into more stable and more efficient therapeutics. 6 , 29 , 171 In the mid-long term, such preclinical studies will surely generate the next generation of mAbs for clinical development.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

Authors are supported by the Ligue contre le Cancer (équipes labelisées), AXA Chair for Longevity Research, Cancéropôle Ile-de-France, Institut National du Cancer (INCa), Fondation Bettencourt-Schueller, Fondation de France, Fondation pour la Recherche Médicale, Agence National de la Recherche, the European Commission (Apo-Sys, ArtForce, ChemoRes. Death-Train) and the LabEx Immuno-Oncology.

Previously published online: www.landesbioscience.com/journals/oncoimmunology/article/22789

Abbreviations:

antibody-dependent cellular cytotoxicity

antibody-dependent cellular phagocytosis

acute lymphoid leukemia

bispecific T-cell engager

complement-dependent cytotoxicity

chronic lymphocytic leukemia

Food and Drug Administration

epidermal growth factor receptor

European Medicines Agency

granulocyte macrophage-colony stimulating factor

interferon α-2b

insulin-like growth factor 1 receptor

interleukin

monoclonal antibody

monomethyl auristatin E

myelodysplastic syndrome

non-Hodgkin lymphoma

non-small cell lung carcinoma

overall survival

pathological complete response

progression-free survival

phosphatidylserine

receptor activator of NFκB ligand

tumor necrosis factor-related apoptosis-inducing ligand receptor 2

total body irradiation

vascular endothelial growth factor

VEGF receptor 2

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