Clinical Status of Bispecific Antibodies

Bispecific antibodies (BsAbs) are artificial antibodies capable of simultaneously binding to two different antigens or epitopes. This enables the recruitment and activation of immune cells, redirection of cytotoxicity, blockade of signaling pathways, or delivery of drugs or radionuclides to specific targets. BsAbs have emerged as a promising therapeutic class, overcoming limitations associated with conventional monoclonal antibodies (mAbs), such as low efficacy, high toxicity, and resistance. Various BsAb types and formats, including quadromas, chemical conjugates, recombinant fragments, and full-length IgGs, with different valencies, specificities, and functionalities, have been developed. Currently, there are over 200 BsAbs in clinical development for treating various diseases. However, the development and approval of BsAbs face challenges, such as optimizing target selection and combination, improving pharmacokinetics and pharmacodynamics, reducing immunogenicity and toxicity, and establishing standardized and scalable production processes.

Bispecific Antibodies in Disease Treatment

BsAbs exhibit great potential and versatility in treating various diseases, particularly cancer, by leveraging mechanisms such as T cell redirection, dual blockade, immune cell recruitment, and targeted delivery. T cell redirection involves using BsAbs to bridge tumor cells and cytotoxic T cells, leading to T cell activation, proliferation, and tumor cell lysis. For instance, blinatumomab, a bispecific T cell engager targeting CD19 and CD3, was approved in 2014 for treating acute lymphoblastic leukemia (ALL), demonstrating remarkable efficacy and survival benefits in clinical trials. Dual blockade utilizes BsAbs to simultaneously inhibit two targets involved in the same or different signaling pathways, resulting in synergistic inhibition of tumor growth and survival. Mosunetuzumab, a full-length IgG BsAb targeting CD20 and CD3, approved in 2020 for non-Hodgkin's lymphoma (NHL), has shown durable responses and manageable toxicity in clinical trials. Immune cell recruitment employs BsAbs to attract and activate various immune cells, enhancing anti-tumor immunity and eliminating tumor cells. Epcoritamab, a full-length IgG BsAb targeting CD20 and CD3, approved in 2021 for NHL, demonstrated high response rates and favorable safety profiles in clinical trials. Targeted delivery uses BsAbs to selectively deliver drugs or radionuclides to tumor cells, increasing efficacy and reducing toxicity. Emicizumab, a full-length IgG BsAb targeting factor IXa and factor X, approved in 2017 for hemophilia A, improved prevention and control of bleeding episodes in clinical trials.

Bispecific Antibodies Targets

BsAb targets are crucial for specificity, efficacy, and toxicity and require careful selection and validation. These targets can be classified into tumor-associated antigens (TAAs) and immune cell receptors (ICRs). TAAs are expressed or overexpressed on tumor cells, serving as tumor-specific markers for BsAbs. ICRs, expressed on immune cells like T cells, NK cells, macrophages, and dendritic cells, can be activated or inhibited by BsAbs as immune modulators. Different combinations of TAAs and ICRs result in various BsAb types with different modes of action and therapeutic effects, such as TAA-TAA, TAA-ICR, or ICR-ICR BsAbs. The selection and validation of BsAb targets depend on factors like target expression level, distribution, and heterogeneity, BsAb affinity and avidity, functional outcomes, cross-reactivity, and the availability and reliability of preclinical and clinical models. The impact of BsAb targets on efficacy and toxicity can be influenced by the tumor microenvironment, immune system, and BsAb pharmacokinetics and pharmacodynamics. Novel and promising BsAb targets include CD47, CD70, and CD123 as TAAs, CD137, CD27, and OX40 as ICRs, and combinations such as PD-1/CTLA-4, CD3/CD28, and CD20/CD47.

References

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