Bispecific Antibodies in Blood Cancers

Mechanism of action of a bispecific T-cell engager (BiTE) connecting a T cell to a target tumor cell

What Are Bispecific Antibodies and How Do They Work in Hematologic Malignancies?

Bispecific antibodies (BsAbs) are engineered immunotherapeutic proteins designed with dual binding specificity. One arm targets a specific tumor-associated antigen on a malignant cell, while the other arm commonly binds the CD3 subunit of the T-cell receptor complex on host cytotoxic T lymphocytes.

By physically bridging these two cells, bispecific antibodies form an artificial immunological synapse. This interaction triggers potent T-cell activation and targeted cytotoxicity via the release of Perforin and Granzymes, operating independently of major histocompatibility complex (MHC) class I antigen presentation.

Most currently approved agents in hematologic oncology are T-cell–engaging bispecific antibodies.

Key therapeutic targets include:

• CD19: Targeted in relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL).
• CD20: Targeted in B-cell non-Hodgkin lymphomas, including follicular lymphoma and diffuse large B-cell lymphoma (DLBCL).
• BCMA (B-Cell Maturation Antigen): Targeted in relapsed/refractory multiple myeloma.
• GPRC5D (G protein-coupled receptor class C group 5 member D): A novel non-BCMA target in multiple myeloma.

Mechanism of action of a BiTE molecule forming an immunological synapse between a cytotoxic T cell and a target cancer cell

Which Blood Cancers Can Bispecific Antibodies Treat?

B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Lymphoblasts on peripheral blood film, a hallmark feature of Acute Lymphoblastic Leukemia (ALL).

Blinatumomab (CD19×CD3): A bispecific T-cell engager (BiTE) indicated for selected patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and minimal residual disease (MRD)-positive B-ALL. As the pioneer bispecific construct, its development established CD19-directed T-cell engagement as a validated therapeutic strategy in acute lymphoblastic leukemia.

B-Cell Lymphomas

Several approved bispecific T-cell engagers target CD20 on malignant B cells and CD3 on cytotoxic T cells:

Mosunetuzumab: Indicated for patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.

Histopathology of follicular lymphoma demonstrating closely packed, effaced lymph node architecture with neoplastic follicles

Glofitamab and Epcoritamab: Indicated for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or large B-cell lymphoma (LBCL).

High-power histopathology of diffuse large B-cell lymphoma (DLBCL) showing sheets of large, atypical lymphoid cells

Odronextamab: Expands the CD20-directed treatment landscape across various B-cell non-Hodgkin lymphomas.

CD20×CD3 bispecific antibodies have demonstrated clinical activity even in heavily pretreated disease, including patients who have experienced disease progression after prior CAR T-cell therapy or autologous stem cell transplantation. These agents differ in their molecular formats, routes of administration (intravenous vs. subcutaneous), dosing schedules, and fixed-duration versus continuous treatment strategies. Specific indications, regulatory approvals, line of therapy, and required toxicity monitoring vary by jurisdiction.

Multiple Myeloma

In multiple myeloma, therapeutic bispecific antibodies focus on two main molecular targets:

BCMA×CD3 (Teclistamab and Elranatamab):

In the pivotal Phase 2 MagnetisMM-3 trial, Elranatamab demonstrated an overall response rate (ORR) of 61.0% with a complete response (CR) rate of 35.0% in triple-class exposed patients naive to BCMA-directed therapy.

In Phase 1/2 clinical evaluation of heavily pretreated, triple-class refractory multiple myeloma, Teclistamab achieved an overall response rate of 63.0% and a median progression-free survival (PFS) of 11.3 months.

Bone marrow aspirate demonstrating abnormal plasma cells typical of multiple myeloma.

GPRC5D×CD3 (Talquetamab):

Targeting G PR-coupled receptor class C group 5 member D (GPRC5D) provides a crucial alternative strategy, particularly for disease that has relapsed following BCMA-directed therapies.

Because GPRC5D is expressed on keratinized epithelial tissues in addition to plasma cells, Talquetamab carries a unique toxicity profile including dysgeusia (taste disturbance), oral mucositis, skin rash, nail dystrophy, and palmar-plantar desquamation. This represents a classic clinical example of “on-target, off-tumor” adverse effects.

Immunohistochemical stain for CD138 demonstrating strong membranous positivity in plasma cells, characteristic of plasma cell myeloma

References:

Dana-Farber Staff. Bispecific Antibodies: How Can They Treat Cancer? Insight (Dana-Farber Cancer Institute). May 20, 2019. Updated March 16, 2023. Available from: https://blog.dana-farber.org/insight/2019/05/how-are-bispecific-antibodies-being-used-to-treat-blood-cancers/

Crombie JL, Graff T, Falchi L, Karimi YH, Bannerji R, Nastoupil L, Thieblemont C, Ursu R, Bartlett N, Nachar V, Weiss J, Osterson J, Patel K, Brody J, Abramson JS, Lunning M, Shah NN, Ayed A, Kamdar M, Parsons B, Caimi P, Flinn I, Herrera A, Sharman J, McKenna M, Armand P, Kahl B, Smith S, Zelenetz A, Budde LE, Hutchings M, Phillips T, Dickinson M. Consensus recommendations on the management of toxicity associated with CD3×CD20 bispecific antibody therapy. Blood. 2024 Apr 18;143(16):1565-1575. doi: 10.1182/blood.2023022432. PMID: 38252906.

Nephron. Micrograph of follicular lymphoma (low magnification) [Digital image on the Internet]. Wikimedia Commons. May 13, 2014 [cited September 28, 2026]. Available from: https://commons.wikimedia.org/wiki/File:Follicular_lymphoma_–_low_mag.jpg

Sayed A, Munir M, Ghazi SM, Ferdousi M, Krishan S, Shaaban A, Habib A, Kola-Kehinde O, Ruz P, Khan S, Sharma S, Meara A, Mahmood S, Feldman S, Yang EH, Kim J, Epperla N, Addison D. Cardiovascular toxicities associated with bispecific T-cell engager therapy. J Immunother Cancer. 2024 Feb 21;12(2):e008518. doi: 10.1136/jitc-2023-008518. PMID: 38388168; PMCID: PMC10882360.

Xue E, Deng X, Doffe F, Kroemer G, Kepp O. Trial Watch – bispecific T cell engagers and higher-order multispecific immunotherapeutics. Oncoimmunology. 2026 Dec 31;15(1):2632421. doi: 10.1080/2162402X.2026.2632421. Epub 2026 Feb 16. PMID: 41700001; PMCID: PMC12915878.

Kumar SK, Callander NS, Adekola K, Anderson LD Jr, Baljevic M, Baz R, Campagnaro E, Castillo JJ, Costello C, D’Angelo C, Devarakonda S, Elsedawy N, Garfall A, Godby K, Hillengass J, Holmberg L, Htut M, Huff CA, Hultcrantz M, Kang Y, Larson S, Lee HC, Liedtke M, Martin T, Omel J, Robinson T, Rosenberg A, Sborov D, Schroeder MA, Sherbenou D, Suvannasankha A, Valent J, Varshavsky-Yanovsky AN, Kumar R, Snedeker J. Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2023 Dec;21(12):1281-1301. doi: 10.6004/jnccn.2023.0061. PMID: 38081133.

Genomic Testing Cooperative. Diffuse Large B-Cell Lymphoma (DLBCL) [Internet]. Genomic Testing Cooperative. [cited September 28, 2026]. Available from: https://genomictestingcooperative.com/diffuse-large-b-cell-lymphoma-dlbcl/

Ludwig H, Terpos E, van de Donk N, Mateos MV, Moreau P, Dimopoulos MA, Delforge M, Rodriguez-Otero P, San-Miguel J, Yong K, Gay F, Einsele H, Mina R, Caers J, Driessen C, Musto P, Zweegman S, Engelhardt M, Cook G, Weisel K, Broijl A, Beksac M, Bila J, Schjesvold F, Cavo M, Hajek R, Touzeau C, Boccadoro M, Sonneveld P. Prevention and management of adverse events during treatment with bispecific antibodies and CAR T cells in multiple myeloma: a consensus report of the European Myeloma Network. Lancet Oncol. 2023 Jun;24(6):e255-e269. doi: 10.1016/S1470-2045(23)00159-6. PMID: 37269857.

Request Online Consultation With Dr M Abdou

Fee: US$100

Secure payment via PayPal (credit and debit cards accepted)

Pay Now