A tri-specific EGFR/cMet/VEGF antibody demonstrates potent multi-mechanistic activity in preclinical triple-negative breast cancer models - research article

Sep 22, 2026

Triple-negative breast cancer (TNBC) remains challenging due to limited therapeutic options and rapid emergence of drug resistance. The study demonstrates that TAVO412, a tri-specific EGFR/cMet/VEGF antibody, can drive antitumor activity in preclinical TNBC models by inhibiting EGFR- and cMet-mediated proliferation, enhancing Fc-mediated effector functions, and suppressing angiogenesis. The dual-epitope anti-EGFR/anti-cMet design shows improved signaling inhibition and cytotoxicity in EGFR-low expressing cell lines compared with a marketed EGFR/cMet bispecific. TAVO412 also exhibits antitumor activity across multiple TNBC cell line-derived xenograft models, supporting its preclinical utility.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Background and unmet needs in TNBC

Target biology: EGFR, cMet, and VEGF signaling crosstalk

Limitations of single-target therapies and anti-VEGF toxicity

Rationale for tri-specific targeting

Multi-targeting to reduce resistance likelihood

TAVO412 design and intended mechanisms

cMet binding, dual EGFR epitopes, and VEGF targeting

Preclinical evidence of activity

RESEARCH ARTICLE A tri-specific EGFR/cMet/VEGF antibody demonstrates potent multi-mechanistic activity in preclinical triple-negative breast cancer models Received for publication, August 18, 2025, and in revised form, April 4, 2026 Published, Papers in Press, April 30, 2026 [https://doi.org/10.1016/j.jbc.2026.1](https://doi.org/10.1016/j.jbc.2026.1)13100 Pu Pu1, Ying Jin1, Songling Zhang1, Yuqiang Xu1, Peng Chen1, Fulai Zhou1, Ping Sun1, Hao Jiang1, Sheng Huang1, Limin Chen 1, Meixia Fu 1, ZhengXia Zha 1, Maria P. MacWilliams 1,2, and Mark L. Chiu 1,2,* From the 1Research & Development Department, Tavotek Biotherapeutics, Suzhou, Jiang Su, China; 2Research & Development, Tavotek Biotherapeutics, Lower Gwynedd, Pennsylvania, USA Reviewed by members of the JBC Editorial Board. Edited by Patrick J. O’Brien Triple negative breast cancer (TNBC) is a cancer with significant unmet medical needs and comprises 10 to 15% of all breast cancers and 15 to 20% of advanced breast cancers due to the limited therapeutic options. Many TNBC tumors are driven by aberrant activities of epidermal growth factor receptor (EGFR), mesenchymal epithelial transition factor (cMet), and vascular endothelial growth factor. We demonstrated how TAVO412, a tri-specific antibody that recognized cMet, dual epitopes of EGFR, and vascular endothelial growth factor could elicit antitumor activity in TNBC. TAVO412 showed inhibition of EGFR- and cMet-mediated tumor proliferation, enhanced Fc-mediated effector functions, and suppression of angiogenesis. The avidity of the dual-epitope based anti-EGFR and anti-cMet design had better signaling inhibition and cytotoxicity against EGFR-low expressing tumor cell lines than the JNJ-61186372 analog, a marketed EGFR/cMet bispecific antibody. Furthermore, TAVO412 exhibited antitumor activities in multiple TNBC cell line-derived xenograft models. Overall, TAVO412 demonstrated great preclinical utility against TNBC. Triple negative breast cancers (TNBCs) are aggressive subtypes of breast cancers lacking the estrogen and progesterone receptors and display low-levels of human epidermal growth factor receptor 2 (1–3). TNBCs account for 10 to 15% of all breast cancers and 15 to 20% of advanced breast cancers, and is associated with rapid progression, early relapse, and limited therapeutic options. Current first-line therapies rely mainly on combination chemotherapy or immune checkpoint blockade, yet TNBC often progresses more rapidly than other subtypes, leading to poor outcomes and limited long-term control (1, 4, 5). A major challenge in TNBC is the high degree of molecular heterogeneity and the rapid emergence of drug-resistant subclones. Single-target therapies—including tyrosine kinase inhibitors (TKIs) and monospecific antibodies-often produce only transient responses before resistance develops through * For correspondence: Mark L. Chiu, [Mark.Chiu@tavotek.com](Mark.Chiu@tavotek.com). target loss, mutation, or compensatory pathway activation. In contrast, multi-targeting agents can suppress parallel oncogenic pathways and reduce the likelihood of simultaneous resistance-conferring mutations, offering a more durable therapeutic approach (6). Many TNBC patients have tumors with increased levels of EGFR, and cMet (7–10). Concomitantly, the activation of the EGFR signaling pathway enhances vascular endothelial growth factor type A (VEGF-A) secretion that then promotes angiogenesis and tumor growth, resistance to EGFR directed therapies such as cetuximab (anti (α)-EGFR mAb), and gefitinib (EGFR TKI), and shorter survival in TNBC patients (11–15). Similarly, cMet overexpression and hepatocyte growth factor (HGF)–mediated activation contribute to resistance to EGFR TKIs and are associated with inferior clinical outcomes (16–19). High-level co-expression of EGFR and cMet in TNBC is associated with significantly worse disease-free survival than expression of EGFR alone. Combined inhibition of EGFR and cMet sign

FAQs

What is the main therapeutic goal of TAVO412 in TNBC?

TAVO412 is designed to simultaneously inhibit EGFR, cMet, and VEGF-driven biology in TNBC to produce a more comprehensive blockade of tumor growth and survival mechanisms.

Which biological activities does TAVO412 demonstrate preclinically?

TAVO412 inhibits EGFR- and cMet-mediated tumor proliferation, enhances Fc-mediated effector functions, and suppresses angiogenesis.

How does TAVO412 compare with an existing EGFR/cMet bispecific antibody in the study?

The study reports that the avidity of TAVO412’s dual-epitope design yields better signaling inhibition and cytotoxicity against EGFR-low expressing tumor cell lines than the JNJ-61186372 analog.

Sep 22, 2026

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