Abstract 1761: SYNB011128: A novel bispecific peptide-drug-conjugate targeting EGFR and CAIX

Abstract Peptide-drug-conjugates (PDCs) are emerging as promising alternatives to antibody-drug-conjugates (ADCs) in oncology. PDCs, with their smaller size (<10 kDa), can offer improved tumor penetration. Additionally, PDCs can potentially exhibit a better safety profile due to their shorter blood PK, absence of an Fc domain, and reduced immunogenicity. Furthermore, PDCs can be entirely chemically synthesized, providing a homogeneous chemical entity. Epidermal Growth Factor Receptor (EGFR) is a key target that is overexpressed in many tumor types. Current EGFR inhibitors primarily focus on mutant forms, creating a treatment gap for tumors with only wild-type overexpression. Carbonic Anhydrase IX (CAIX) represents another cancer-specific marker that supports tumor survival in hypoxic or acidic conditions and is frequently co-overexpressed with EGFR in cancers such as non-small cell lung cancer (NSCLC), head and neck cancers, and pancreatic cancers. SYNB011128, a bispecific PDC, exhibits high affinity and specificity for binding both EGFR and CAIX. Upon internalization, SYNB011128 releases MMAE, a potent tubulin inhibitor, through linker cleavage by tumor-specific proteases. In total, SYNB011128 employs three primary anti-cancer mechanisms: 1) Competing with EGF to inhibit the EGFR pathway. 2) Inhibiting CAIX enzyme function, crucial for cancer cell survival in hypoxic environments and resistance clone development. 3) Delivering the cytotoxic MMAE payload. Preclinical studies showed that SYNB011128 achieved complete tumor regression in multiple pancreatic and colon cancer models, outperforming EGFR-antibody-drug conjugates (EGFR-ADCs). Additionally, SYNB011128 showed efficacy in models of Osimertinib-resistant non-small cell lung cancer (NSCLC). With a molecular weight of 4 kDa, SYNB011128 exhibited rapid and deep tumor penetration. PDC induced biomarker was detected in both the periphery and core of the tumor within 6 hours post-dosing. Despite its relatively short blood half-life, SYNB011128 ensured sustained accumulation of the payload within tumors. This pharmacokinetic profile may reduce on-target toxicity and enhance safety. In mouse studies, SYNB011128 demonstrated no adverse effects, such as weight loss or liver/kidney damage, after 28 days of treatment at doses that induced tumor regression. Chemically, SYNB011128 is synthesized as a single enantiomer, without diastereomeric isomers. In summary, PDC SYNB011128 effectively targets both EGFR and CAIX, utilizing multiple anti-cancer mechanisms and achieving deep tumor penetration, which may lead to robust clinical efficacy. By binding to two cancer antigens to enhance tumor selectivity over normal tissues, and a pharmacokinetic profile of sustained tumor accumulation vs a short blood half-life, SYNB011128 may also have an improved safety margin. Citation Format: Caihong Zhou, Michael Poss, Cheng Lu, Ruochi Zhang, Yu Wang, Yuanpeng Xiong, Xin Gao, Xiao Zhang, Yan Degenhardt. SYNB011128: A novel bispecific peptide-drug-conjugate targeting EGFR and CAIX [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1761.