Comprehensive Guide to Bispecific Antibodies in Immunotherapy

Bispecific antibodies (BsAbs) are recombinant molecules that represent a revolutionary advancement in genetic engineering for cancer immunotherapy. They offer the unique ability to bind two distinct targets simultaneously. These dual approaches enhance various molecular structures [1, 2, 3]. Several FDA-approved drugs are available for treating cancer diseases. Therefore, this article will explore the critical bispecific antibodies in the current world, including their molecular mechanisms, target selection rationale, and clinical development status.

Potential biosimilars (ichorbio's products are available in the links) are Glofitamab, Mosunetuzumab, and Epcoritamab [4, 5] 

These antibodies target CD20 and CD3 based on the proven success of rituximab (anti-CD20) and the potent cytotoxic potential of T-cell engagement through CD3. The choice of CD20 as a target reflects its stable expression on B-cells and minimal internalization upon antibody binding. 

• Clinical Status: FDA approved (2023)
• Current Indications: *Approved for relapsed/refractory large B-cell lymphoma
  *Phase III trials for follicular lymphoma (NCT04981171)
  *Phase II for CLL/SLL (NCT05057494)
• Design Rationale: 2:1 configuration enables enhanced avidity for CD20, potentially improving efficacy in low CD20-expressing tumors

• Clinical Status: FDA approved (2022)
• Current Indications: *Approved for relapsed/refractory follicular lymphoma
  *Phase III for diffuse large B-cell lymphoma (NCT05171647)
• Design Rationale: Optimized binding kinetics reduce cytokine release syndrome while maintaining efficacy

• Clinical Status: FDA approved (2023)
• Current Indications: *Approved for relapsed/refractory large B-cell lymphoma
  *Phase III trials for follicular lymphoma (NCT04663347)
• Design Rationale: Subcutaneous administration and Fc engineering for reduced systemic toxicity

Potential biosimilars (ichorbio's products are available in the links) are Blinatumomab and Elranatamab [6] 

• Clinical Status: FDA approved (2014)
• Current Indications: *Approved for B-cell ALL and MRD+ B-cell precursor ALL
  *Phase III for newly diagnosed ALL (NCT02003222)
• Target Selection Rationale: CD19 was chosen for consistent expression across B-cell development stages; CD3 engagement enables potent T-cell activation

• Clinical Status: Phase III
• Current Trials: *Phase III for relapsed/refractory multiple myeloma (NCT04959864)
  *Phase II for newly diagnosed multiple myeloma (NCT04989972)
• Target Selection Rationale: BCMA (B-cell maturation antigen) is highly expressed in myeloma cells with limited expression in normal tissues; CD3 engagement provides direct T-cell cytotoxicity

Potential biosimilars (ichorbio's products are available in the links) are Vudalimab and Cadonilimab [7]. 

• Clinical Status: Phase III
• Current Trials: *Phase III for metastatic castration-resistant prostate cancer (NCT04956874)
  *Phase II for various solid tumors (NCT05308329)
• Target Selection Rationale: Simultaneous blockade of complementary immune checkpoint pathways to enhance T-cell responses

• Clinical Status: Phase III
• Current Trials: *Phase III for cervical cancer (NCT04974269)
  *Phase II for hepatocellular carcinoma (NCT04932877)
• Target Selection Rationale: Combines immune checkpoint inhibition with anti-angiogenic effects to address tumor microenvironment

Potential biosimilars (ichorbio's products are available in the links) are Amivantamab, Teclistamab, and Istiratumab [8] 

• Clinical Status: FDA approved (2021)
• Current Indications: *Approved for EGFR exon 20 insertion mutation-positive NSCLC
  *Phase III for various EGFR-mutated cancers (NCT04487080)
• Target Selection Rationale: Dual targeting addresses primary and bypass resistance mechanisms in EGFR-mutated cancers

• Clinical Status: FDA approved (2022)
• Current Indications: *Approved for relapsed/refractory multiple myeloma
  *Phase III for newly diagnosed multiple myeloma (NCT05318547)
• Target Selection Rationale: *BCMA was chosen for its essential role in plasma cell survival and restricted expression pattern
  *CD3 engagement enables targeted T-cell-mediated cytotoxicity
  *The combination provides potent anti-myeloma activity with a manageable toxicity profile

Potential biosimilars (ichorbio's products are available in the links) are Faricimab, Cibisatamab, and Bavunalimab [8, 9] 

• Clinical Status: FDA approved (2022)
• Current Indications: * Approved for wet AMD and DME
  * Phase III for retinal vein occlusion (NCT04740931)
• Target Selection Rationale: Dual inhibition of VEGF and Ang2 pathways provides superior vessel stability and reduced edema

• Clinical Status: Phase II
• Current Trials: * Phase II for colorectal cancer (NCT04826003)
• Target Selection Rationale: CEA selected for high expression in epithelial cancers; CD3 enables T-cell engagement

• Clinical Status: Phase I/II
• Current Trials: * Phase I/II for advanced solid tumors (NCT04895761)
• Target Selection Rationale: Novel immune cell engagement strategy beyond traditional T-cell activation

Potential biosimilars (ichorbio's products are available in the links) are Talquetamab and Gresonitamab [10, 11] 

• Clinical Status: FDA approved (2023)
• Current Indications: *Approved for relapsed/refractory multiple myeloma
  *Phase III trials ongoing (NCT05455320)
• Target Selection Rationale: *GPRC5D was chosen as a novel target expressed in myeloma cells
  *Provides an alternative to BCMA-targeting therapies
  *Limited expression on healthy tissues reduces off-target effects

• Clinical Status: Phase I
• Current Trials: *Phase I for advanced solid tumors (Trial ID pending)
• Target Selection Rationale: *Novel target combination under investigation

• Structural integrity maintenance
• Dual binding validation
• Stability assessment
• Biological activity verification
• Immunogenicity evaluation

• Target expression levels and specificity
• Binding affinity optimization
• T-cell activation regulation
• Cytokine release management
• Administration route optimization
• Patient selection strategies

The bispecific antibody landscape continues to evolve rapidly, with many molecules achieving regulatory approval and others showing promising clinical results. Understanding the rationale behind target selection and clinical development strategies is crucial for researchers and clinicians.

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2.   Gu Y, Wang Z, Wang Y. Bispecific antibody drug conjugates: Making 1+1>2. Acta Pharm Sin B. 2024 May;14(5):1965-1986. doi: 10.1016/j.apsb.2024.01.009. Epub 2024 Jan 20. PMID: 38799638; PMCID: PMC11119582.

3.      https://www.fda.gov/drugs/spotlight-cder-science/bispecific-antibodies-area-research-and-clinical applications#:~:text=Bispecific%20antibodies%20(BsAbs)%20have%20two,of%20the%20same%20antigen%20simultaneously. [Extracted information on 5 November 2024]

4.   Jin S, Liu Y, Zhang Y, Zhou F, You L, Zhang J. Bispecific T cell engagers targeting CD20/CD3 in B-cell lymphoma: latest updates from 2023 EHA annual meeting. Ther Adv Chronic Dis. 2023 Dec 4; 14:20406223231215701. doi: 10.1177/20406223231215701. PMID: 38058395; PMCID: PMC10697048.

5.   Liu X, Zhao J, Guo X, Song Y. CD20 × CD3 bispecific antibodies for lymphoma therapy: latest updates from ASCO 2023 annual meeting. J Hematol Oncol. 2023 Aug 3;16(1):90. doi: 10.1186/s13045-023-01488-4. PMID: 37537626; PMCID: PMC10401875.

6.   Omer MH, Shafqat A, Ahmad O, Alkattan K, Yaqinuddin A, Damlaj M. Bispecific Antibodies in Hematological Malignancies: A Scoping Review. Cancers (Basel). 2023 Sep 14;15(18):4550. doi: 10.3390/cancers15184550. PMID: 37760519; PMCID: PMC10526328.

7.   Zhang T, Lin Y, Gao Q. Bispecific antibodies targeting immunomodulatory checkpoints for cancer therapy. Cancer Biol Med. 2023 Mar 24;20(3):181–95. doi: 10.20892/j.issn.2095-3941.2023.0002. PMID: 36971124; PMCID: PMC10038071.

8.   Guo X, Wu Y, Xue Y, Xie N, Shen G. Revolutionizing cancer immunotherapy: unleashing the potential of bispecific antibodies for targeted treatment. Front Immunol. 2023 Dec 1; 14:1291836. doi: 10.3389/fimmu.2023.1291836. PMID: 38106416; PMCID: PMC10722299. 

9.    Panos GD, Lakshmanan A, Dadoukis P, Ripa M, Motta L, Amoaku WM. Faricimab: Transforming the Future of Macular Diseases Treatment - A Comprehensive Review of Clinical Studies. Drug Des Devel Ther. 2023 Sep 18; 17:2861-2873. doi: 10.2147/DDDT.S427416. PMID: 37746113; PMCID: PMC10516184.

10.  Chari A, Minnema MC, Berdeja JG, Oriol A, van de Donk NWCJ, Rodríguez-Otero P, Askari E, Mateos MV, Costa LJ, Caers J, Verona R, Girgis S, Yang S, Goldsmith RB, Yao X, Pillarisetti K, Hilder BW, Russell J, Goldberg JD, Krishnan A. Talquetamab, a T-Cell-Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma. N Engl J Med. 2022 Dec 15;387(24):2232-2244. doi: 10.1056/NEJMoa2204591. Epub 2022 Dec 10. PMID: 36507686.

11.  https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI%20Thesaurus&code=C184829 [Extracted information on 5 November 2024]