September 2024: Bispecific Antibodies in Oncology

Bispecific antibodies are rapidly transforming the therapeutic landscape, especially in oncology and autoimmune diseases. Such recombinant molecules can bind to two different antigens at the same time, offering greater specificity in targeting disease pathways. Since their introduction, the area of bispecifics has held tremendous promise in oncological cancers like multiple myeloma and lymphomas. Recent drug approvals like Ordspono have further cemented the role of bispecific antibodies in fighting relapsed and refractory cancers, in addition to bispecific formats such as T-cell engagers.

Recent Approvals and Pipeline Advances

• Aug 26: European Commission approved Regeneron’s novel bispecific Ordspono (odronextamab). It is a hinge-stabilized, fully human IgG4-based CD20×CD3 bispecific designed to bridge CD20 on cancer cells with CD3-expressing T cells to facilitate local T-cell activation and cancer-cell killing, approved for relapsed or refractory (R/R) follicular lymphoma (FL) or R/R diffuse large B-cell lymphoma (DLBCL).

• Sep 3: The FDA has granted fast track designation to Innovent’s IBI363 for the treatment of unresectable locally advanced or metastatic melanoma that has progressed following at least 1 line of systemic therapy, including a PD-(L)1 inhibitor. IBI363 is an investigational PD-1/IL-2α bispecific antibody fusion protein.

• Sep 6: Adaptin Bio emerges from stealth with a cleared investigational new drug application with the FDA for its glioblastoma treatment. APTN-101 is a brain bispecific T-cell engager (BRiTE).

• Sep 8: Positive Phase 3 results for Akeso and Summit Therapeutics’ ivonescimab, a novel PD-1/VEGF bispecific. Results show it slashed the risk of disease progression or death by an incredible 49% compared with Merck’s Keytruda in patients with non-small cell lung cancer (NSCLC).

Meanwhile in the research space, bsAbs are being used to advance precision oncology. A recent review describes how manipulating bsAb structures allows generation of multiple formats to optimize molecular function for specific clinical contexts, such as through multispecific antibodies, the incorporation of new antigen targets, or even bispecific antibody–drug conjugates. In addition, a possible strategy to enhance bsAb target specificity is to deplete endogenous cells expressing the targeted tumor antigen before bsAb administration.

However, the toxicities associated with the use of bsAbs need bespoke management strategies and expertise in clinical use. Understanding mechanisms of resistance to bsAbs is crucial to rational combination regimens or sequencing with other therapeutics to improve patient outcomes.

Another recent review describes bispecific antibodies specifically in the treatment of multiple myeloma. While monoclonal antibodies like daratumumab along with proteasome inhibitors (PI)s, and immune modulators (IMiD)s have significantly improved survival, they also cause unique challenges at the time of relapse. Engaging immune T cells for tumour cell kill with chimeric antigenic T-cell (CAR T-cell) therapy and bispecific antibodies have become important therapeutic options in relapsed multiple myeloma. 

Bispecific antibodies have proven to induce deep and durable responses in heavily pre-treated myeloma patients with a predictable safety profile and the ease of off-the-shelf availability. Significant research is ongoing to overcome resistance mechanisms like T cell exhaustion, target antigen mutation or loss and high disease burden. Various trials are also studying these agents as first line options in the newly diagnosed setting. These agents play an important role in the relapsed setting, and efforts are underway to optimize their sequencing in the myeloma treatment algorithm.

Besides multiple myeloma, bsAbs are being studied to treat large B-cell lymphomas. A recent analysis demonstrates that bsAbs are generally well-tolerated and effective in adults with LBCL. BsAbs appear to have superior tolerability, but inferior efficacy to CAR T-cell therapies in adults with LBCL. Future research on safety and efficacy should focus on evaluating adverse event timing and management, the impact on the patient’s quality of life, the burden on the healthcare system, and overall survival outcomes.