Abstract Background: Antibody drug conjugate (ADC) has proven an effective drug modality and keeps evolving with innovations explored on each of its components. However, the potential coordination between the antibody and the payload of an ADC is usually overlooked efficacy-wise. Here we introduce the development of a novel panRAS (ON) inhibitor payload and more importantly, the Functional Antibody and Synergistic conjugate(FASconTM), a novel ADC design which employes the antibody-payload synergy to further enhance the therapeutic activity of an ADC beyond precision delivery. The preclinical profile of an exemplified FAScon GFS784, an EGFR-panRASi ADC is presented for concept demonstration. Methods: GFS784 was established by conjugating Cetuximab with a panRAS(ON) inhibitor GF005095 via a proprietary, cleavable linker at DAR of 8. The anti-growth activity of GFS784 was tested in cell lines with different RAS genotypes. The bystander effect of GFS784 was investigated by comparing its effect on the growth of an EGFR negative cell line when mono-cultured or co-cultured with an EGFR-positive cell line. The plasma stability of GFS784 was studied via incubation in vitro or injection into mice. CDX tumor mouse models were used to explore the in vivo efficacy of GFS784. Results: The pan-RAS(ON) inhibitor payload GF005095 employes cyclophilin A to target K/H/N-RAS mutants or wild type proteins and demonstrated higher anti-growth activity than DXd in vitro. GFS784 bound to and was internalized into tumor cells in an EGFR-dependent manner. GFS784 showed broad and potent anti-proliferation activity in EGFR-expressed tumor cell lines addicted to mutant or wild type RAS genes with a sub-nanomolar median IC50, which is significantly lower than that of an EGFR-DXd ADC. GFS784 demonstrated significant bystander effect in vitro. GFS784 showed good plasma stability when tested in vitro and in animals. GFS784 at dose levels of 1-5 mg/kg via i.v., q3W showed robust therapeutic efficacy in RAS-mutant CDX models which were either sensitive or resistant to the DXd counterpart. Compared with combination therapy using Cetuximab and RMC-6236 at clinical equivalent doses, GFS784 demonstrated comparable efficacy but better tolerability in CDX mice. GFS784 also induced deep tumor regression in both Osimertinib-sensitive and resistant EGFR-mutant NSCLC CDX models. Conclusions: GFS784 has a satisfactory preclinical profile as an ADC candidate. GFS784 is effective in CDX models resistant to DXd ADC or Osimertinib, suggesting the potential as a next-generation ADC and an alternative solution for TKI resistance. Therefore, GFS784 provides a promising solution for treating RAS mutant or EGFR-altered tumors and a further clinical investigation is warranted. Citation Format: Feng Yan, Jichen Zhao, Jingyang Zhang, Li Wang, Yumei Li, Siyuan Le, Fusheng Zhou, Jiong Lan, Qiang Lu. GFS784, a next-generation ADC with a novel panRAS(ON) inhibitor payload abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4536.
Yan et al. (Fri,) studied this question.