From Biomarkers to Breakthroughs: Targeting MUC16 and B7-H3 to Combat Solid Tumors

Solid tumors present significant challenges in oncology, often resisting conventional treatments. Biocytogen is pioneering next-generation therapies by developing fully human antibodies that precisely target MUC16 and B7-H3—molecules frequently overexpressed in various solid tumors. This targeted approach aims to enhance tumor specificity and minimize off-target effects, offering new hope in the fight against cancer.

Understanding the Therapeutic Targets

MUC16 (CA125): Beyond a Biomarker

Mucin 16 (MUC16), also known as cancer antigen 125 (CA125), is a high-molecular-weight transmembrane glycoprotein belonging to the mucin family. It plays a crucial role in protecting and lubricating epithelial surfaces. However, in various cancers such as ovarian, pancreatic, and triple-negative breast cancers, MUC16 is frequently overexpressed. This overexpression contributes to tumor growth and progression by promoting cell proliferation, metastasis, and immune evasion (Felder et al., 2014) (Giamougiannis, Pierre, and Francis, 2021). 

MUC16 Overexpression Stimulates Tumor Cell Division (Saad et al., 2022) 

MUC16 undergoes proteolytic cleavage, shedding its large extracellular domain and leaving the membrane-proximal (MP) fragment anchored to the cell surface. This retained MP fragment presents an attractive target for antibody-based interventions, as it enables selective recognition of tumor cells while minimizing off-target effects associated with the cleaved, soluble form of MUC16.

MUC16 Structure (Aithal et al., 2018)

Fully Human Anti-MUC16 Antibodies at Biocytogen: Precision-Targeted Cancer Therapeutics

Leveraging its proprietary RenNano and RenLite mouse platforms, Biocytogen has developed fully human heavy-chain antibodies (HCAbs) and monoclonal antibodies (mAbs) targeting MUC16. Both HCAbs and mAbs are designed to bind the membrane-proximal (MP) region of MUC16—the portion that remains attached to the tumor cell surface following cleavage. By targeting this retained region, the antibodies avoid binding to the soluble form of MUC16 shed into the bloodstream, thereby improving tumor specificity and minimizing off-target interactions.

Key Advantages

• Improved Tumor Specificity: Minimizes off-target effects by targeting membrane-bound MUC16.

• High Binding Affinity: HCAbs bind human and monkey MUC16 with nanomolar affinities (~10⁻⁸–10⁻⁹ M).

• Robust Tumor Cell Binding: Strong binding to MUC16-positive tumor cell lines, notably the OVCAR-3 ovarian cancer cell line.

• Comparable Binding Profiles to Benchmark Antibodies:  REGN-5668 analog (PC1) and Sofituzumab vedotin analog (PC2).

Fully Human Anti-MUC16 Heavy-Chain Antibodies (HCAbs) at Biocytogen

B7-H3 (CD276): A Promising Immune Checkpoint Target

B7-H3 (CD276) is an immune checkpoint molecule from the B7 family that has emerged as a compelling target in cancer immunotherapy. While its expression is low in normal tissues, B7-H3 is overexpressed in various solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), triple-negative breast cancer (TNBC), ovarian cancer, and colorectal cancer. This overexpression contributes to tumor immune evasion by inhibiting T-cell activation and proliferation, thereby suppressing the body's natural immune response against cancer cells. 

Beyond its immunosuppressive role, B7-H3 also promotes tumor progression through non-immunological mechanisms. It has been implicated in enhancing tumor cell proliferation, metastasis, angiogenesis, and resistance to therapies. These multifaceted functions make B7-H3 a promising therapeutic target. Current strategies under investigation include monoclonal antibodies, antibody-drug conjugates, and chimeric antigen receptor (CAR) T-cell therapies aimed at inhibiting B7-H3 function or expression (Chapoval et al., 2001) (Kontos et al., 2021).

mAbs and Engineered Engagers Targeting B7-H3 (Bottino et al., 2023)

Advancing B7-H3-Targeted Therapies: Fully Human Antibodies from Biocytogen

High Affinity and Internalization—No Engineering Required

The RenMab-derived anti-B7-H3 mAbs exhibit strong affinity for both human and monkey B7-H3, rivaling the benchmark DS-7300 analog. These antibodies also show robust internalization activity, a critical step for delivering payloads like antibody-drug conjugates (ADCs)—and notably, this was achieved without the need for in vitro antibody engineering, underscoring the strength of Biocytogen’s platform.

Common Light Chain Antibodies for Bispecific Assembly

A second class of B7-H3-targeting mAbs was generated from RenLite KO mice, specifically designed for common light chain (CLC) applications. Among these, 16 mAbs showed high affinities ranging from 8 × 10⁻⁸ to 5 × 10⁻¹⁰ M for human B7-H3, and 9 × 10⁻⁸ to 3 × 10⁻⁹ M for monkey B7-H3. 7 candidates demonstrated notable internalization activity within 24 hours. These CLC antibodies can be flexibly assembled into bispecific formats, enabling combinatorial targeting strategies with other RenLite-derived antibodies. 

Explore Our Pipeline

In addition to MUC16 and B7-H3, Biocytogen is advancing fully human antibodies against a range of highly sought-after targets, including CD71 (TFR1), CDH17, TROP2, FOLR1, FAP, and EGFR. Contact us to explore evaluation, licensing, or co-development opportunities!

Unlock Innovative Therapeutic Opportunities with Biocytogen

At Biocytogen, we are redefining the future of antibody discovery with our cutting-edge RenMice^® platforms. Our expertise spans the discovery of fully human monoclonal, bispecific, multispecific, Hu-VHH, TCR-mimic antibodies, and bispecific ADCs.

Through our proprietary platforms, we offer global partners access to an extensive off-the-shelf library featuring over 1 million fully human antibody sequences against approximately 1,000 targets. As of December 31, 2024, Biocytogen has successfully established over 200 therapeutic antibody and clinical asset co-development, out-licensing, and transfer agreements worldwide.

Reference:

About MUC16

Felder, Mildred, et al. "MUC16 (CA125): tumor biomarker to cancer therapy, a work in progress." Molecular cancer 13 (2014): 1-15.

Giamougiannis, Panagiotis, Pierre L. Martin-Hirsch, and Francis L. Martin. "The evolving role of MUC16 (CA125) in the transformation of ovarian cells and the progression of neoplasia." Carcinogenesis 42.3 (2021): 327-343.

Saad, Hebatallah M., et al. "The potential role of MUC16 (CA125) biomarker in lung cancer: a magic biomarker but with adversity." Diagnostics 12.12 (2022): 2985.

Aithal, Abhijit, et al. "MUC16 as a novel target for cancer therapy." Expert opinion on therapeutic targets 22.8 (2018): 675-686.

Liu, J. F., et al. "Phase I study of safety and pharmacokinetics of the anti-MUC16 antibody–drug conjugate DMUC5754A in patients with platinum-resistant ovarian cancer or unresectable pancreatic cancer." Annals of Oncology 27.11 (2016): 2124-2130.

Moore, Kathleen N., et al. "First-in-human phase 1/2 study of ubamatamab, a MUC16xCD3 bispecific antibody, administered alone or in combination with cemiplimab in patients with recurrent ovarian cancer." (2023): TPS5624-TPS5624.

About B7-H3

Chapoval, Andrei I., et al. "B7-H3: a costimulatory molecule for T cell activation and IFN-γ production." Nature immunology 2.3 (2001): 269-274.

Kontos, Filippos, et al. "B7-H3: an attractive target for antibody-based immunotherapy." 

Bottino, Cristina, et al. "B7-H3 in pediatric tumors: far beyond neuroblastoma." Cancers 15.13 (2023): 3279.

Doi, T., et al. "453O DS-7300 (B7-H3 DXd antibody-drug conjugate [ADC]) shows durable antitumor activity in advanced solid tumors: Extended follow-up of a phase I/II study." Annals of Oncology 33 (2022): S744-S745.