T-cell-engaging bispecific antibodies in cancer

The present and future of bispecific antibodies for cancer therapy.

Abstract Immune cell engagers are engineered antibodies with at least one arm binding a tumor-associated antigen and at least another one directed against an activating receptor in immune effector cells: CD3 for recruitment of T cells and CD16a for NK cells. The first T cell engager (the anti-CD19 blinatumomab) was approved by the FDA in 2014, but no other one hit the market until 2022. Now the field is gaining momentum, with three approvals in 2022 and 2023 (as of May): the anti-CD20 × anti-CD3 mosunetuzumab and epcoritamab and the anti-B cell maturation antigen (BCMA) × anti-CD3 teclistamab, and another three molecules in regulatory review. T cell engagers will likely revolutionize the treatment of hematological malignancies in the short term, as they are considerably more potent than conventional monoclonal antibodies recognizing the same tumor antigens. The field is thriving, with a plethora of different formats and targets, and around 100 bispecific T cell engagers more are already in clinical trials. Bispecific NK cell engagers are also in early-stage clinical studies and may offer similar efficacy with milder side effects. Trispecific antibodies (engaging either T cell or NK cell receptors) raise the game even further with a third binding moiety, which allows either the targeting of an additional tumor-associated antigen to increase specificity and avoid immune escape or the targeting of additional costimulatory receptors on the immune cell to improve its effector functions. Altogether, these engineered molecules may change the paradigm of treatment for relapsed or refractory hematological malignancies. 

Bi- and trispecific immune cell engagers for immunotherapy of hematological malignancies

New immune cell engagers for cancer immunotherapy.

Bispecific T-cell engagers (BiTEs) and bispecific antibodies (BiAbs) have revolutionized the treatment landscape of hematological malignancies. By directing T cells towards specific tumor antigens, BiTEs and BiAbs facilitate the T-cell-mediated lysis of neoplastic cells. The success of blinatumomab, a CD19xCD3 BiTE, in acute lymphoblastic leukemia spearheaded the expansive development of BiTEs/BiAbs in the context of hematological neoplasms. Nearly a decade later, numerous BiTEs/BiAbs targeting a range of tumor-associated antigens have transpired in the treatment of multiple myeloma, non-Hodgkin’s lymphoma, acute myelogenous leukemia, and acute lymphoblastic leukemia. However, despite their generally favorable safety profiles, particular toxicities such as infections, cytokine release syndrome, myelosuppression, and neurotoxicity after BiAb/BiTE therapy raise valid concerns. Moreover, target antigen loss and the immunosuppressive microenvironment of hematological neoplasms facilitate resistance towards BiTEs/BiAbs. This review aims to highlight the most recent evidence from clinical trials evaluating the safety and efficacy of BiAbs/BiTEs. Additionally, the review will provide mechanistic insights into the limitations of BiAbs whilst outlining practical applications and strategies to overcome these limitations.

Bispecific Antibodies in Hematological Malignancies: A Scoping Review

Although many patients with diffuse large B cell lymphoma (DLBCL) may achieve a complete response to frontline chemoimmunotherapy, patients with relapsed/refractory disease typically have poor outcomes. Odronextamab, a CD20xCD3 bispecific antibody that provides “signal 1” through the activation of the T cell receptor/CD3 complex, has exhibited early, promising activity for patients with highly refractory DLBCL in phase 1 trials. However, not all patients achieve complete responses, and many relapse, thus representing a high unmet medical need. Here, we investigated whether adding a costimulatory “signal 2” by engaging CD28 receptors on T cells could augment odronextamab activity. We demonstrate that REGN5837, a bispecific antibody that cross-links CD22-expressing tumor cells with CD28-expressing T cells, enhances odronextamab by potentiating T cell activation and cytolytic function. In preclinical DLBCL studies using human immune system–reconstituted animals, REGN5837 promotes the antitumor activity of odronextamab and induces intratumoral expansion of reprogrammable T cells while skewing away from a dysfunctional state. Although REGN5837 monotherapy shows limited activity and no toxicity in primate studies, it augments T cell activation when dosed in combination with odronextamab. In addition, analysis of non-Hodgkin lymphoma clinical samples reveals an increase in CD28+CD8+ T cells after odronextamab treatment, demonstrating the presence of a population that could potentially be targeted by REGN5837. Collectively, our data demonstrate that REGN5837 can markedly enhance the antitumor activity of odronextamab in preclinical NHL models, and the combination of these two bispecific antibodies may provide a chemotherapy-free approach for the treatment of DLBCL. Description REGN5837, a CD22xCD28 bispecific antibody, enhances the antitumor activity of odronextamab in preclinical models of diffuse large B cell lymphoma. Dynamic bispecific duo Bispecific antibodies are being used for cancer immunotherapy because they target two different antigens thus facilitating T cell targeting to tumors. Odronextamab is a CD20xCD3 bispecific antibody that shows promising activity in patients with diffuse large B cell lymphoma (DLBCL), but not all patients achieve complete responses, and there remains a high unmet need in the setting of relapsed/refractory disease. Wei et al. (p. 0000) demonstrate that REGN5837, a CD22xCD28 bispecific antibody, enhanced the antitumor activity of odronextamab in preclinical models of DLBCL and that the combination exhibited no toxicity in primates while augmenting T cell activation. CD28+CD8+ T cells were expanded in non-Hodgkin lymphoma samples from a phase 1 odronextamab trial, suggesting that addition of REGN5837 could enhance antitumor activity. These findings highlight the potential clinical usefulness of a bispecific antibody combination for treating DLBCL.

CD22-targeted CD28 bispecific antibody enhances antitumor efficacy of odronextamab in refractory diffuse large B cell lymphoma models

V-set and immunoglobulin domain-containing 4 (VSIG4) is a complement receptor of the immunoglobulin superfamily that is specifically expressed on tissue resident macrophages, and its many reported functions and binding partners suggest a complex role in immune function. VSIG4 is reported to have a role in immune surveillance as well as in modulating diverse disease phenotypes such as infections, autoimmune conditions, and cancer. However, the mechanism(s) governing VSIG4's complex, context-dependent role in immune regulation remain elusive. Here, we identify cell surface and soluble glycosaminoglycans (GAGs), specifically heparan sulfates, as novel binding partners of VSIG4. We demonstrate that genetic deletion of heparan sulfate synthesis enzymes or cleavage of cell-surface heparan sulfates reduced VSIG4 binding to the cell surface. Furthermore, binding studies demonstrate that VSIG4 interacts directly with heparan sulfates, with a preference for highly sulfated moieties and longer GAG chains. To assess the impact on VSIG4 biology, we show that heparan sulfates compete with known VSIG4 binding partners C3b and iC3b. Further, mutagenesis studies indicate this competition occurs through overlapping binding epitopes for heparan sulfates and complement on VSIG4. Together these data suggest a novel role for heparan sulfates in VSIG4-dependent immune modulation.

/pdf/vsig4-interaction-with-heparan-sulfates-inhibits-vsig4-ecw4a4ii.pdf

VSIG4 interaction with heparan sulfates inhibits VSIG4-complement binding.

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CD22-targeted CD28 bispecific antibody enhances antitumor efficacy of odronextamab in refractory diffuse large B cell lymphoma models

VSIG4 interaction with heparan sulfates inhibits VSIG4-complement binding.