Portfolio News
GFS784 monotherapy showed comparable anti-tumor efficacy and superior safety versus RMC-6236 plus anti-EGFR antibody combination
In three week animal studies, low dose of GFS784 (5–10 mg/kg, Q3W) achieved anti tumor efficacy comparable to the combination of low dose RMC-6236 (10 mg/kg, QD) plus cetuximab. A weekly administration of GFS784 (5 mg/kg, QW) elicited even more pronounced activity, matching the anti-tumor effect combining high dose RMC-6236 (25 mg/kg, QD) plus cetuximab.
Across all dose levels tested over three weeks, GFS784 maintained stable body weight in animals with no substantial weight loss, and the relative change in body weight (RCBW) was significantly superior to the RMC- 6236 plus cetuximab combination regimen.
Broad patient potential: common activity preserved in RAS-mutant, EGFR-mutant, TKI-resistant and DXd insensitive models
The payload of GFS784 is a molecular glue Pan RAS (ON) inhibitor that acts via a CypA-GF005095-RAS complex, inhibiting most activated wild type and mutant RAS isoforms. While the single agent of cetuximab targets a broad patient population with EGFR alterations, the dual RAS/EGFR inhibition delivers pathway synergy potentially covering 50-90% of patients with non small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC).
In EGFR-mutant NSCLC animal models, single dose administration of GFS784 over three weeks exerted consistent, dose dependent anti tumor activity in multiple osimertinib-sensitive and -resistant models, including models harboring concurrent TKI resistance and cMET amplification. GFS784 also demonstrated dose dependent anti-tumor activity, even in DXd insensitive tumor models in a three week experiment.
FAScon™: functional antibodies and synergistic targeted payloads to transform ADC therapeutic index and reduce adaptive resistance
The FAScon™ platform is engineered to pioneer the next generation of ADCs by evolving carrier antibodies into functional antibodies and replacing cytotoxic payloads with synergistic targeted payloads. The platform strategically integrates large- and small-molecule inhibitors that modulate complementary signaling pathways, an approach poised to boost therapeutic efficacy, overcome potential resistance, and inspire next-generaiton ADC development.
GFS784, derived from the FAScon™ platform, is the world’s first ADC employing a molecular glue Pan RAS inhibitor as its targeted payload. Beyond its therapeutic potential, preclinical data highlighted favorable safety properties of GFS784, demonstrating a prolonged half-life in tumor tissue and a short half-life in circular system. Coupled with potent bystander effect, this safety profile enhanced therapeutic efficacy while lowering off-target risks. The unique delivery of targeted payload would further circumvent potential toxicities, which are usually observed with oral RAS inhibitors.
FAScon™ is a globally innovative ADC platform that combines functional antibodies with mechanistically synergistic targeted payload, upgrading traditional carrier antibodies into functional antibodies to link with targeted payloads instead of cytotoxic payloads. It aims to transform next generation ADC development with improved efficacy, wider therapeutic index, and the ability to overcome resistance. Starting with mechanistically synergistic ADCs targeting the RAS pathway, the platform will expand into other signaling pathways and disease areas beyond oncology.
GFS784 utilizes a synergistic RAS+EGFR dual target mechanism, pairing a molecular glue Pan RAS (ON) inhibitor payload with cetuximab (anti EGFR antibody). It potently inhibits RAS mutant, EGFR mutant, and TKI resistant tumors, and suppresses tumor growth in both DXd sensitive and DXd insensitive ADC models. Additionally, GFS784 shows excellent cell membrane permeability to support robust bystander killing, and maintains high potency in cytotoxic resistant cell lines at picomolar concentrations. It also demonstrates favorable safety characteristics in preclinical evaluations.
