Abstract LB229: ALM-401: A first-in-class next generation bispecific ADC configured to deliver superior efficacy in selected solid tumor indications

Abstract There is growing interest in exploiting bispecific approaches for the design of next generation ADCs to improve therapeutic efficacy, increase therapeutic window and overcome drug resistance. ALM-401 is a highly selective, engineered bispecific ADC (bsADC) Candidate Drug targeting the tumor associated antigens ROR1 and EGFR. ALM-401 is designed to deliver enhanced efficacy in solid tumor indications and an improved toxicity profile versus canonical ADCs to these clinically established targets. ROR1 and EGFR were identified as a top target pairing for a bsADC using a proprietary bioinformatics engine, OmniaScape™. The two proteins are co-expressed across a high percentage of patients from a range of solid tumor indications including NSCLC, renal and gastro-oesophageal cancers, with little to no co-expression on normal adult tissue. Importantly, mechanistic data supports a direct interaction between ROR1 and EGFR biology to promote tumorigenesis and drug resistance, including rapid regeneration of ROR1 on the surface of cancer cells following target engagement, an attractive property for a bsADC target. ALM-401 exploits a single domain antibody (sdAb)-Fc format which engages ROR1 and EGFR in a monovalent fashion, with site-specific conjugation of the clinically proven vcMMAE payload providing a homogeneous DAR4 bsADC. The smaller sdAb format provides enhanced tumor penetration versus a standard IgG antibody. Bispecific binding provides enhanced internalisation into dual positive NSCLC cells leading to highly potent cell killing with little effect on normal human epidermal keratinocytes (which express high levels of EGFR). ALM-401 exerts a strong bystander effect (to overcome tumor heterogeneity) and MMAE is a potent inducer of immunogenic cell death. Additionally, the payload was selected to overcome the potential ILD toxicities associated with TOP1i ADCs. These important design features translate into outstanding anti-tumor efficacy in CDX models of EGFR mutant and wild-type NSCLC, with complete and durable regressions achieved at low doses. Importantly, ALM-401 is significantly more efficacious than zilovertamab vedotin, the lead ROR1 ADC in clinical development. In a series of NSCLC PDX models, ALM-401 delivers a transformational efficacy profile in dual positive models exhibiting a range of ROR1 and EGFR expression by IHC, with an ORR of 100% (9/9). This bsADC significantly outperforms a zilovertamab vedotin biosimilar, which exhibits an ORR of 22% (2/9) in these models at the same payload equivalent dose. ALM-401 has excellent plasma stability, a PK profile in line with approved ADCs, and good overall manufacturing and developability characteristics, with the potential to deliver significantly improved patient outcomes across a range of solid tumor indications with high unmet need. Citation Format: Graham Cotton, Chiara Saladino, Jennifer Thom, Aaron N. Cranston, Mark Wappett, Stacey Dodd, Paul Trumper, Aidan McCann, Georgiana Parau, Andrew Porter, Caroline Barelle, Estelle G. McLean, Tim Harrison. ALM-401: A first-in-class next generation bispecific ADC configured to deliver superior efficacy in selected solid tumor indications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB229.