Amanitin-Based Fc-Small Molecule-Drug Conjugates with Noncleavable Linker: A Novel Therapeutic Strategy for Prostate Cancer Targeted Therapy.

Prostate cancer remains a major global health burden, with limited options and poor prognosis in advanced stages. To extend survival and improve the quality of life for patients, targeted therapies have become an emerging treatment modality. Antibody-drug conjugates (ADC) have shown huge clinical success but only limited therapeutic effects in prostate cancer as their large size limits tumor penetration. Small molecule-drug conjugates (SMDC), consisting of a small molecule as a binding moiety and a cytotoxic drug, offer advantages due to their smaller size, but their short plasma half-life and poor efficacy have hampered their clinical breakthrough so far. Fragment crystallizable (Fc)-grafted SMDCs (Fc-SMDC) combine a SMDC with the half-life-extending Fc fragment of an antibody. So far, the Fc fragments have been attached directly to the small molecule-drug complex, making an enzymatic cleavable linker for payload release an indispensable prerequisite. We report a first-in-class Fc-SMDC targeting PSMA and carrying α-amanitin with a noncleavable linker. The payload is conjugated directly to the Fc region via an engineered cysteine to separate it from the targeting moiety. This approach enables, in contrast to conventional Fc-SMDCs, the use of noncleavable linkers for minimal premature drug release, increased plasma stability, and low systemic toxicity. Due to the noncleavable linker, our conjugate showed high tolerability and an extended half-life, resulting in prolonged tumor exposure and excellent antitumor efficacy in xenograft models. Together with the favorable tolerability in non-human primates, these findings highlight the potential for a next-generation treatment for prostate cancer.