Abstract 6580: A Novel EGFR x cMET bispecific ADC PRO1286 demonstrated broad antitumor activity and promising tolerability in preclinical models

耐受性 医学 癌症研究 肿瘤科 药理学 不利影响
作者
Xiao Yang,Haiyu Huang,Jianhe Yin,Xuan Qiu,Lei Wang,Haidong Liu,Baiteng Zhao,Chen Zhu
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:84 (6_Supplement): 6580-6580
标识
DOI:10.1158/1538-7445.am2024-6580
摘要

Abstract EGFR and cMET are frequently co-expressed on tumor cells, often upregulated as the escape mechanism for each other, and both well-validated targets in oncology. Small molecule TKIs and amivantamab have been approved for non-small cell lung cancer with relevant actionable genomic alterations (AGA), and monoclonal antibodies offer treatment options for EGFR-expressing head and neck and colorectal cancers without AGA. Yet high unmet need in these tumors still exists. We sought to develop an EGFR and cMET dual-targeting ADC using our proprietary technology platform with carefully chosen design features for the many tumors expressing EGFR and cMET with or without AGA. PRO1286 is comprised of a monovalent bispecific human IgG1 (dubbed as “Bsab”) with fine-tuned affinity on EGFR and cMET, and the proprietary topoisomerase 1 inhibitor-based linker-drug, sesutecan. Sesutecan previously demonstrated promising characteristics in preclinical studies with multiple targets and conferred an encouraging benefit:risk profile in the clinic with a FRα-directed ADC (rinatabart sesutecan). PRO1286 at DAR8 displays high hydrophilicity and excellent stability and developability in vitro. PRO1286 binds selectively and specifically to each target with a low nanomolar EC50 in the CHO-K1 cells overexpressing each target. PRO1286 exhibited efficient internalization (~50-80% internalized in 4 hrs) and strong cytotoxicity (sub-nanomolar IC50) against a broad panel of tumor cell lines with higher potency than the parent mAbs. PRO1286 produced marked and dose dependent anti-tumor activity in mouse xenograft models encompassing a wide range of target expression levels, tumor types (head and neck, lung, esophageal, gastric, colorectal), and genomic landscape (with or without AGA in EGFR or cMET; with diverse additional co-mutations). Sustained tumor growth inhibition or complete remission was observed in several xenograft models after treatment with a single dose (2 mg/kg) of PRO1286. PRO1286 was more efficacious than benchmarking molecules in the mouse studies. In an exploratory toxicity study in cynomolgus monkeys, PRO1286 was well tolerated at 30 mg/kg with the main toxicity being payload-driven and residing in bone marrow. PRO1286 exhibited a stable PK profile that was similar to that of the Bsab in rats and favorable PK characteristics in monkeys. In summary, PRO1286 demonstrated promising physiochemical properties, PK/PD, antitumor activity, and tolerability in preclinical studies. It may carry an expanded therapeutic index compared to other EGFR- and/or cMET-directed ADCs. It may also differentiate from existing EGFR- and/or cMET-targeting agents on broad coverage of EGFR and cMET-expressing tumors with or without the respective AGAs. Effort is under way to advance a DAR optimized molecule to the clinic for the treatment of many EGFR- or cMET-expressing solid tumors. Citation Format: Yang Xiao, Haiyu Huang, Jianhe Yin, Xuan Qiu, Lei Wang, Haidong Liu, Baiteng Zhao, Zhu Chen. A Novel EGFR x cMET bispecific ADC PRO1286 demonstrated broad antitumor activity and promising tolerability in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6580.

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