Antifolate ADCs, a novel linker-drug platform for targeted therapy with a clear differentiating mechanism of action

Background: Clinical resistance to dominant ADC payloads - topoisomerase-I inhibitors and tubulin inhibitors - is increasing, underscoring the need for novel payloads with a differentiated mechanism of action (MoA). Methotrexate (MTX), a pioneering antifolate, revolutionized oncology and autoimmune disease treatment but suffers from poor tumor selectivity and systemic toxicity. Despite its clinical validation, MTX and related antifolates have not been successfully adapted into targeted therapies. Byondis revisited the class of antifolates and optimized these to a proprietary novel linker-drug platform currently in IND-enabling studies. Results: Byondis developed a first-in-class antifolate linker-drug platform, featuring optimized payloads with a low- to sub-nanomolar potency and suitable for linker coupling. The resulting optimized payload demonstrates potent inhibition of dihydrofolate reductase (DHFR), in vitro cytotoxicity in a broad panel of cell lines, minimal affinity for resistance-associated transporters (BCRP, PGP), and favorable physicochemical properties allowing for the ongoing GMP-scale up of the linker-drug (LD) and good ADC manufacturability. The selected optimized linker contains a glucuronide moiety with the aim to improve the therapeutic index. The PhysChem properties of the LD demonstrates / ensures minimal impact on ADC hydrophobicity after conjugation and perfectly allows its use in a future dual payload approach. The Byondis' lead antifolate ADC is based on the novel antifolate LD platform. This antifolate ADC is based on a yet undisclosed tumor antigen targeting antibody. It shows strong in vitro cytotoxicity across a broad tumor cell-line panel and in a deruxtecan insensitive cell-line. Robust in vivo efficacy in NSCLC and HNSCC patient-derived xenograft models is demonstrated, with no significant toxicity at doses resulting in tumor regressions. The antifolate ADC delivers optimal pharmacokinetics and anti-tumor activity. GMP manufacturing of the linker-drug is underway. Conclusions: The antifolate platform reintroduces a clinically validated MoA into the ADC landscape with enhanced selectivity, potency, and manufacturability. Its orthogonal MoA offers potential across different tumor types including an advantage in overcoming resistance to existing ADCs and supports sequential ADC therapy. With broad applicability across tumor types, antifolate-based ADCs are poised to address unmet clinical needs and are ready for clinical translation.