Bispecific Antibodies Targeting CD3 and BCMA

Introduction of CD3

CD3 is part of the T cell receptor complex (TCR), consisting of four different polypeptide chains: CD3γ, CD3δ, CD3ε, and CD3ζ. The CD3 gene is located on human chromosome 11. The main function of CD3 is to mediate the interaction between the TCR and the major histocompatibility complex (MHC) molecule on antigen-presenting cells, thereby activating T cells. CD3 is expressed on all mature T cells, making it an important marker for T cells. CD3 plays a key role in many immune-related diseases, such as autoimmune diseases, organ transplant rejection, and cancer. Bispecific antibodies targeting CD3 can utilize the cytotoxic ability of T cells while recognizing another antigen on tumor cells, thus achieving tumor immunotherapy.

Introduction of BCMA

BCMA is the abbreviation for B cell maturation antigen, also known as TNFRSF17 (tumor necrosis factor receptor superfamily member 17). BCMA is a transmembrane protein, encoded by the TNFRSF17 gene located on human chromosome 16. BCMA is mainly expressed on plasma cells and is an important regulator of B cell development and plasma cell survival. BCMA can bind to two ligands, namely BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand), and activate downstream signaling pathways. BCMA is overexpressed in various B cell malignancies, especially in multiple myeloma (MM), making it a potential target for MM therapy. Bispecific antibodies targeting BCMA can also bind to CD3 on T cells, thereby enabling T cells to recognize and kill BCMA-positive tumor cells.

Signaling Pathways Involved in Bispecific Antibodies Targeting CD3 and BCMA

Bispecific antibodies targeting CD3 and BCMA are a novel immunotherapy strategy that can simultaneously bind to CD3 on T cells and BCMA on tumor cells, forming an immunological synapse, activating T cells, and inducing tumor cell apoptosis. This strategy involves multiple signaling pathways, including:

• TCR signaling pathway: After binding to CD3, bispecific antibodies can mimic the interaction between the TCR and MHC molecules, thereby activating the TCR signaling pathway. This pathway includes the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) on the CD3ζ chain and downstream signaling molecules such as ZAP-70, LAT, PLC-γ1, IP3, DAG, Ca2+, PKC-θ, NF-κB, NFAT, and AP-1. The activation of the TCR signaling pathway can promote T cell proliferation, differentiation, and effector functions.
• BCMA signaling pathway: After binding to BCMA, bispecific antibodies can block the binding of BCMA to its normal ligands BAFF and APRIL, thereby inhibiting the BCMA signaling pathway. This pathway includes the phosphorylation of TNF receptor-associated factor (TRAF) binding sites on the intracellular domain of BCMA, and downstream signaling molecules such as NF-κB, JNK, and ERK. The inhibition of the BCMA signaling pathway can reduce tumor cell survival and drug resistance.

Fig.1 Schematic of key tumor targets and the mechanism of action of BsAbs in multiple myeloma (Caraccio C, 2020)

Clinic Status of Bispecific Antibodies Targeting CD3 and BCMA

Bispecific antibodies targeting CD3 and BCMA are a novel immunotherapy approach for multiple myeloma (MM), which currently has several candidates in different stages of clinical trials, and one of them has received accelerated approval from the U.S. Food and Drug Administration (FDA).

So far, only one bispecific antibody targeting CD3 and BCMA has received accelerated approval from the FDA, which is Abecma (blenrepamab), developed by Celgene. It was approved on March 26, 2021, for the treatment of patients with relapsed or refractory MM after at least four prior therapies. It is a CAR-T cell therapy, which uses gene engineering technology to make the patient's own T cells express a bispecific antibody that can recognize both CD3 and BCMA. It showed good efficacy and safety in the DREAMM-2 trial, with an overall response rate of 73%, a median duration of response of 11 months, and common adverse reactions including cytokine release syndrome, infection, anemia, etc.

Currently, there are several bispecific antibodies targeting CD3 and BCMA in different phases of clinical trials, mainly developed by Janssen, Regeneron, Amgen, Pfizer, etc. These drugs are all constructed by protein engineering technology and can be directly injected intravenously to the patients.

Table 1. Bispecific Antibodies Targeting CD3 and BCMA in Clinical Trials

As seen from the table, these drugs have shown promising results in heavily pretreated patients with MM, with high response rates and many deep responses. However, the durability of these responses remains to be established, and more data is needed to compare the efficacy and safety of these drugs.

References

1. Cipkar C, et al. Antibodies and bispecifics for multiple myeloma: effective effector therapy. Hematology Am Soc Hematol Educ Program. 2022;2022(1):163-1721
2. Lancman G, et al. Bispecific Antibodies in Multiple Myeloma: Present and Future. Blood Cancer Discov. 2021 Sep 1;2(5):423-4332
3. Caraccio C, et al. Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions. Front Immunol. 2020 Apr 24;11:501.
4. Garfall AL, et al. Chimeric antigen receptor T cells in myeloma. Blood. 2018 Oct 4;132(14):1526-15344
5. Tai YT, et al. Targeting B-cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-based immunotherapy. Front Immunol. 2018 Aug 10;9:18215
6. Cho SF, et al. Targeting B cell maturation antigen (BCMA) in multiple myeloma: rationale and current evidence. Drugs Context. 2019 Feb 18;8:212540.
7. Cohen AD, et al. B cell maturation antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) for multiple myeloma (MM). J Clin Oncol. 2017 May 20;35(15_suppl):3010-3010.
8. Usmani SZ, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016 Jul 7;128(1):37-44.
9. Madduri D, et al. Teclistamab in Relapsed or Refractory Multiple Myeloma: Updated Results from a Phase I Study of Subcutaneous Delivery and a Novel Pentaspecific Format (PentaTEC). Blood Cancer Discov (2021) DOI: 10.
10. Madduri D, et al. REGN5458, a BCMA x CD3 bispecific monoclonal antibody, induces deep and durable responses in patients with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol 38: 2020 (suppl; abstr 8504).
11. Harrison SJ, et al. AMG701, an anti-B-cell maturation antigen (BCMA) half-life extended bispecific T-cell engager (HLE BiTE®) immune therapy, in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Updated results. J Clin Oncol 38: 2020 (suppl; abstr 8505).
12. Shah N, et al. PF-06863135, a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): Updated results from a phase I study. J Clin Oncol 38: 2020 (suppl; abstr 8506).