HDP-103, a PSMA targeting amanitin-based ADC, is efficacious even in difficult to treat patient derived xenograft models with heterogenous PSMA expression

Background Antibody drug conjugates (ADCs) are increasingly used in the treatment of solid tumors. HDP 103 is an anti PSMA ATAC (amatoxin based ADC) targeting metastatic castration resistant prostate cancer (mCRPC). ATACs offer distinct advantages over conventional ADCs: i) inhibition of RNA polymerase II confers activity in both proliferating and quiescent cells; ii) there are no known resistance mechanisms; iii) ATACs are potent against target low cancer cells; and iv) ATACs show particular good efficacy in patients with 17p/TP53 deletion who have poor prognosis. This study presents preclinical data demonstrating HDP 103 efficacy and a favorable therapeutic window in difficult to treat mCRPC patient derived xenograft models with heterogeneous PSMA expression. Materials and Methods HDP 103: anti-PSMA ADC with site specific, cysteine conjugated amatoxin linker. Immunofluorescence: IF on PDX tumors using HDP 103 antibody. Efficacy: subcutaneous prostate cancer PDX models treated intravenously with HDP 103 q14d × 3. Tolerability: cynomolgus monkeys dosed intravenously on days 1 and 22; PK sampling, necropsy, and histopathology performed. PK/PD: two compartment model with parallel linear and Michaelis-Menten elimination. Results HDP 103 produced potent, durable tumor remissions and significantly extended survival in PDX models at doses ≤5 mg/kg, including models with del(17p) and heterogeneous PSMA expression. In cynomolgus monkeys, HDP 103 was well tolerated, causing only transient changes in serum chemistry and hematology, and exhibited a half life of approximately 5-10 days. No salivary gland toxicity was observed; microscopic adverse findings were limited to the kidney. Integrated PK/PD modeling of efficacy and tolerability predicted serum exposures and patient dose ranges consistent with a convenient therapeutic window. Conclusion HDP 103, an anti PSMA ATAC for the treatment of mCRPC, demonstrates robust and durable antitumor activity in PDX models representative of the target population, including tumors with heterogeneous PSMA expression and those harboring a del(17p). Combined with a favorable half life and a manageable safety profile in nonhuman primates, HDP 103 warrants further clinical development as a novel treatment option for mCRPC, particularly for patients with del(17p) with a high unmet medical need.