Abstract 6342: Preclinical safety & pharmacokinetics of AFVT-2101, a tetravalent FRα x CD16A bispecific innate cell engager for the treatment of solid tumors

AFVT-2101 is a novel bispecific innate immune cell engager in development to treat solid tumors. It is comprised of bivalent folate receptor alpha (FRα) and CD16A (FcγRIIIA) binding domains with a silenced IgG1 Fc region. AFVT-2101 is engineered to exert potent and selective immune-mediated antitumor activity with minimal off-tumor toxicity by promoting NK cell and macrophage engagement of FRα-positive tumors. A comprehensive package of IND-enabling studies is currently in progress to support the preclinical safety profile of AFVT-2101. In agreement with target sequence homology, binding affinity of AFVT-2101 against human and cynomolgus monkey FRα and CD16A is highly similar, confirming non-human primate (NHP, specifically cynomolgus monkey) as the only pharmacologically relevant preclinical safety model. The toxicology program includes tissue cross-reactivity assessment against a panel of human and cynomolgus cryosections, single- and repeat-dose range finding (DRF) non-GLP studies and a 4-week IND-enabling GLP study with 4-week recovery period in NHPs. In a single-dose study AFVT-2101 demonstrated non-linear pharmacokinetics when administered as a 2-h IV infusion to male NHPs where the mean Cmax (85.1 and 1620 µg/mL) and AUC168hr (3,430 and 97,000 µg.h/mL) at 3 and 30 mg/kg, respectively, increased supra-proportionally with respect to dose, consistent with target-mediated drug disposition. Half-life was 103-155 h across doses. A DRF study was conducted to characterize toxicity, identify target organs, determine toxicokinetics (TK), immunogenicity (anti-drug antibodies, ADA), and to inform the dose selection of the subsequent 4-week study. AFVT-2101 was administered once-weekly to female NHPs via 2-h IV infusion for a total of 4 doses. Mean Cmax (1120, 3320, 7190 µg/mL) and AUC168hr (83,600, 209,000, 592,000 µg.h/mL) at 30, 75, and 150 mg/kg, respectively, increased in a generally dose-proportional manner with a trend for modest accumulation (