Introduction
Immunology and oncology landscapes are intricately linked to each other. This has been known since the twentieth century but recent decade has seen remarkable advances in the field of immuno-oncology. The various ways the immune system can be harnessed to fight cancer are by checkpoint inhibition, ex vivo manipulation of immune cells or by redirecting endogenous immune cells toward specific targets. An example of directing endogenous immune cell to specific targets is bispecific antibodies which are the subject of this review.
Methodology
Relevant studies of all the currently approved bispecific antibodies were reviewed and summarized. Clinical application and indications per current national guidelines were reviewed and summarized to help a practicing physician be able to understand the current treatment landscape of bispecific antibodies.
Pharmacology
Bifunctional/bispecific antibodies are antibody molecules in which one arm targets a T cell surface molecule, such as CD3 and the other one, a specific tumor antigen. The theory is that the tumor specific arm of the antibody binds to the tumor and the T cell specific arm binds to the T cell. The physical juxtaposition of the tumor cell and the T cells is believed to lead to a tumor-cell lysis, T cell activation, and the release of cytokines that have a direct negative effect on the tumor cells or recruit other effector cells of host defense into the tumor [ 1 ], shown in Fig. 1 . Several bifunctional antibodies have been approved by the FDA or the European Medicine agency, and others are in development. Fig. 1 Simple diagram depicting mechanism of action of bispecific antibodies
An antibody is a glycosylated protein complex that is synthesized and secreted by immune B cells, usually in response to the exposure of the immune system to “foreign” or “non-self” molecules, such as infectious agents or transplanted tissues. On binding to the “foreign” molecule, the antibody triggers an immune response to the infected cells. An antibody contains four proteins (or polypeptide chains): two heavy chains and two light chains. These chains make up variable domains (which bind the target antigen) and constant domains, which mediate downstream events including complement fixation and antibody dependent cellular cytotoxicity.
A monoclonal antibody is an antibody that has a defined specificity (i.e., it binds a specific epitope on a specific antigen) and is derived from a single, immortalized B cell clone.
Cytotoxicity of bispecific antibodies results from simultaneous binding of a tumor-associated antigen and the endogenous T cells, triggering T cells activation with release of toxic granules such as granzyme B and perforin [ 2 ].
There are 2 main types of bifunctional antibodies.
The first has binding specificity for a tumor-associated antigen on one arm and on the other arm, binding specificity for an activating receptor expressed by the T cells (usually CD3). These are often called bifunctional T cell engagers (BiTEs).
Blinatumomab, glofitamab, and epcoritamab are some of the examples and are discussed further below.
The second type targets two antigens (each arm targets a single antigen) in a single tumor cell activation pathway. An example is amivantamab which targets epidermal growth factor receptor & the oncoprotein cMet and is used in the treatment of non-small cell lung cancers with a specific mutation in the EGFR gene.
Adverse effects of special interest
Common reported toxic effects of T cell engaging therapies are cytokine release syndrome (CRS) and neurotoxic effects, though these appear to be less severe with CD20 X CD3 bispecific agents than with the most CAR-T Cell therapies.
Grade 3 and 4 CRS is defined as one requiring vasopressors or Oxygen requirement > 40% fiO2, life threatening condition, is usually less than 1% and up to 4% with glofitamab (possibly due to 2 CD20 binding domains) [ 3 – 5 ]. Grade 3 and 4 CRS incidence with CAR-T cell therapy, on the other hand, can be up to 28% [ 6 , 7 ].
Successful mitigation strategies for CRS with t cell engaging bispecific agents include prephase anti-CD20 monoclonal antibody to deplete non-malignant B cells and decrease initial bispecific occupancy on nonmalignant and malignant B cells, the use of step-up doses over a period of 3 weeks, premedication with glucocorticoids and subcutaneous administration.
BiTEs should be discontinued and high-dose steroids started for grade 3 and 4 CRS. Supportive care with vasopressors and oxygen support would be needed. Patients should not be re challenged after they have had a grade 4 CRS. Cautious rechallenge can be attempted after grade 3 CRS.
Immune effector cell-associated neurotoxicity syndrome (ICANS) is a clinical and neuropsychiatric syndrome that can occur in the days to weeks following administration of certain types of immunotherapy, especially immune effector cell (IEC) and T cell engaging therapies. ICANS is typically associated with CAR-T cell therapy. Its frequency and pattern are less well characterized. The incidence of any grade of ICANS is < 10% as explained separately with each agent below.
ICANS occurs in context of CRS and commonly presents within 3–4 days of developing CRS manifested with neurological symptoms ranging from altered mental status, seizures. Treatment consists primarily of steroids and anti-seizure medications.
Rarely prolonged cytopenias, febrile neutropenia and serious infections including Covid-19 have also observed [ 2 ].
Bispecific antibody T cell engagers in diffuse large b cell lymphoma
Currently BiTEs are approved in DLBCL in second or later relapse, and the two approved drugs are glofitamab and epcoritamab which are both CD20XCD3 bispecific antibody.
Glofitamab was studied in a phase 2 trial. There are 154 patients with relapsed/refractory aggressive B cell lymphoma (71% DLBCL), who had received at least 2 lines of therapy, with 1/3rd of patient having undergone CAR-T cell therapy [ 5 ]. Patients received pretreatment with obinutuzumab to mitigate cytokine release syndrome, followed by fixed-duration glofitamab monotherapy (12 cycles total). Glofitamab was associated with 52% overall response rate (ORR) including 39% complete response (CR) and 37% 12-month progression-free survival (PFS). Response was durable—3/4th of the patient who achieved CR continues to be in remission at 12 months. 62% had grade 3 or higher adverse events (AEs) including 4% CRS and ICANS in 3%.
Epcoritamab was studied in a multicenter phase 2 trial [ 8 ]. One hundred and fifty-seven adults with r/r CD20-positive large B cell lymphoma and ≥ 2 prior lines of therapy including 39% who received CAR-T cell therapy were treated till progression or unacceptable toxicity. The overall response rate was 63.1%, and complete response rate was 38.9%. The median duration of response was 12.0 months. Grade ≥ 3 CRS occurred in 3 percent and ICANS in 6.4% with one death.
Bispecific antibody T cell engagers in Multiple Myeloma
Currently, 3 BiTEs are approved in multiple myeloma (MM) in patients who have progressed on anti-CD38 monoclonal antibody, lenalidomide, pomalidomide, bortezomib, carfilzomib, a patient population that is also called penta refractory. This patient population generally has a poor prognosis with limited options of treatment until recently. Now BiTEs as well as CAR-T cell therapy are available for this patient population. BiTEs appear to have similar efficacy with better tolerability although they have not been compared. BiTEs have only been studied in single arm trials so far unlike CAR—T cell therapy. BiTes seem to be a better option in a rapidly progressing disease due to off the shelf nature unlike longer time required to begin CAR-T cell therapy and limited availability in only tertiary care centers.
Teclistamab and elranatamab are bispecific monoclonal antibodies directed at BCMA on the tumor and CD3 on the patient’s T cells. Talquetamab is a bispecific monoclonal antibody directed at GPRC5D on the tumor and CD3 on the patient’s T cells.
Teclistamab was studied in a single arm phase 1/2 multicenter trial in 165 patients with relapsed refractory MM who had received at least three prior therapies including anti-CD38 monoclonal antibody, proteasome inhibitor, immunomodulatory inhibitor and had not received into BCMA-targeted therapy [ 9 ]. ORR of 63%, 39% CR was noted. DOR was 18 month, estimated PFS 11 months and median OS was 18 months. Infectious (45% grade 3 or 4) and hematologic (grade 3/4 neutropenia, anemia and thrombocytopenia in 64%, 37% and 21%, respectively) were noted. CRS and ICANS were uncommon. There are 0.6% grade 3 CRS and no grade 3/4 ICANS.
Elranatamab was studied in a phase 2 single arm trial [ 10 ]. One hundred and twenty-three patients with relapsed or refractory MM had received at least three prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent, but no BCMA-targeted therapy was treated with elranatamab. The overall response rate was 61 percent with 35 percent complete response. CRS occurred in 58% of patient, all of which were grade 1 or 2. ICANS occurred in only 3.4 percent of patient; all were grade 1 or 2. Infectious toxicity was more common with 40% grade 3 or 4.
Talquetamab was studied in a phase 1/2 uncontrolled trial [ 11 ]. One hundred patients with MM patients who had received at least 3 prior therapies including anti-CD38 monoclonal antibody, proteasome inhibitor and immunomodulator agent were treated with Talquetamab. ORR 73%with a median DOR of 9.5 months was noted after a median follow-up of 14 months.
Bispecific antibody T cell engagers in Follicular B cell lymphoma
Mosunetuzumab, a CD20xCD3 BiTE is approved by in relapsed follicular lymphoma patients who have received at least 2 prior systemic therapy.
It was studied in a single arm phase 2 study where there are 90 patients with relapsed refractory FL who had received at least two prior systemic therapies (median 3) including an anti-CD20 agent, alkylating agent and autologous HCT (21%) [ 12 ]. Treatment with mosunetuzumab leads to an ORR of 80%, CR 60%, DOR of 23 months and PFS of 18 months. CRS was predominantly observed in first cycle, and grade 3 and above was only noted on 2 out of 90 patients (0.2%). Most common grade 3 and higher adverse effects were neutropenia, hypophosphatemia.
Bispecific antibody T cell engagers in Acute Lymphoblastic Leukemia (ALL)
Blinatumomab is a CD19xCD3 BiTE approved for treatment of relapsed or refractory pH-negative or pH-positive B cell ALL.
It was studied in a randomized phase 3 trial where 405 relapsed refractory pH-negative ALL patients were randomized to either blinatumomab or cytarabine-based therapy [ 13 ]. Blinatumomab in comparison with chemotherapy was associated with a higher rate of OS (7.7 vs 4 months; HR 0.71, 95% CI 0.55 0 9.93), CR (34% vs 16%) and EFS at 6 months (31% vs 12%, HR 0.55 with 95% CI 0.43–0.71). EFS at six months (31 vs 12 percent; HR for relapse or death after achieving CR 0.55; 95% CI 0.43–0.71). Grade 3/4 toxicity in both arms was comparable. CRS was noted in < 5% of patients.
Bispecific antibody T cell engagers in Small cell cancer
Tarlatamab is a bispecific T cell engager directed against Delta-like ligand 3 and CD3. Delta-like ligand 3 is over expressed in 90% of small cell cancer. It was studied in a phase 2 study in 220 patient with small cell cancer with a median of 2 prior treatments [ 14 ]. It showed a response rate of 40%. Among patients with an objective response, duration of response was 6 months in 59% patients. Median progression-free survival was 4.9 months. Overall survival rates at 9 months were 66. CRS was noted in 51% of patient, primarily in treatment cycle 1. Grade 3 CRS occurred in 1% of patients. 3% of patients discontinued treatment because of side effects.
Bispecific antibody T cell engagers in Uveal melanoma
Tebentafusp is a bispecific gp100 peptide-HLA-directed CD3 T cell engager indicated for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. In a phase 3 trial of treatment naive metastatic uveal ca patients expressing HLA-A*02:01were randomized to be treated with Tebentafusp vs investigator’s choice of treatment (pembrolizumab, ipilimumab, dacarbazine) [ 15 ]. Treatment with Tebentafusp compared to investigator’s choice showed better overall survival (median OS 22 months vs 16 months), PFS (31% vs 19%) CRS occurred in 89% of patients with only 1% with grade 3 or above.
Bispecific antibody T cell engagers in Prostate ca
BiTEs targeting PSMA have been studied in metastatic castrate resistant prostate ca. Drugs including pasotuxizumab, acapatamab have shown efficacy in phase 1 trials, and currently, the focus is AMG 340 [ 16 ]. None are FDA-approved yet.
Bispecific antibody T cell engagers in solid malignancies expressing EPCAM
Catumaxomab is a cd3*EPCAM BiTE which was withdrawn from market in 2017 due to unacceptable CRS and hepatotoxicity.
Conclusion
Immunotherapy has changed the treatment landscape of cancer in the past decade. Amongst various forms of immunotherapy, manipulating the T cell has shown promise in past few years. T cell manipulation can be done by CAR-T cell therapy or bispecific antibodies. These 2 therapeutic modalities have been studied and shown efficacy in hematologic malignancies in relapsed refractory setting. They have not been compared to each other in randomized control trials; hence, the adequate sequencing is not known. Although cross-trial comparison is not ideal, available evidence indicates toward similar efficacy and better tolerability of BiTEs compared to CAR-T cell therapy [ 4 , 9 , 17 , 18 ]. Bispecific antibodies, though, have an advantage of being able to be used in an “off the shelf” manner considering these are not MHC specific and can be administered to all patients regardless of HLA type. Also, BiTEs do not require the patient to be lymphodepleted. CAR-T cell therapy due to logistical issues is only available at tertiary care centers and require a lot of social support. Hence, practically it is not available to a large section of population living in rural settings as well as often for patients from lower socio economic background.
For these reasons, BiTEs seem to be a more desired and logical treatment option in relapsed refractory settings, when the disease is often progressing rapidly and patient do not have time for a time consuming therapy like CAR-T cell therapy to be initiated. CAR-T cell therapy is a powerful tool, but it seems that with recent developments, BiTEs provide us and our patients with yet another effective line of an treatment in some relapsed refractory hematologic malignancies before we use CAR-T cell therapy.
BiTEs efficacy in solid malignancies is yet unproven. The widespread expression of tumor-associated antigens (against which BiTEs could be targeted) on off-target normal body tissues probably presents a potential for widespread adverse effects. Tumor masses/solid malignancies also tend to have high interstitial pressure which hampers penetration by high molecular mass molecules like BiTEs.
Publisher's Note
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Author’s contribution
V.V. and G.S. wrote the main manuscript text and prepared Fig. 1 . All authors reviewed the manuscript.
Funding
The authors have not disclosed any funding.
Data availability
No datasets were generated or analyzed during the current study.
Declarations
Conflict of interest
The authors declare no competing interests.
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