ABSTRACT
Purpose Most prostate cancer (PCa) patients treated with androgen receptor (AR)-signaling inhibitors develop therapeutic resistance due to restoration of AR-functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized monoclonal antibody specifically targeting free prostate-specific antigen (KLK3).
Experimental Design LNCaP-AR xenografts (NSG mice) and KLK3_Hi-Myc transgenic mice were imaged with 89Zr- or treated with 90Y- or 225Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma-counting, positron emission tomography (PET), autoradiography and microscopy. Therapeutic efficacy of [225Ac]hu5A10 and [90Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [89Zr]hu5A10 in non-human primates (NHP) were determined using PET.
Results Biodistribution of radiolabeled hu5A10-constructs was comparable in different mouse models. Specific tumor uptake increased over time and correlated with PSA expression. Treatment with [90Y]/[225Ac]hu5A10 effectively reduced tumor burden and prolonged survival (p≤0.0054). Effects of [90Y]hu5A10 were more immediate than [225Ac]hu5A10 (TTN, p<0.0001) but less sustained (TTP, p<0.0001). Complete responses were observed in 7/18 [225Ac]hu5A10 and 1/9 mice [90Y]hu5A10. Pharmacokinetics of [89Zr]hu5A10 were consistent between NHPs and comparable to those in mice. [89Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period.
Conclusions We present a complete preclinical evaluation of radiolabeled hu5A10 in mouse PCa models and NHPs, and establish hu5A10 as a new theranostic agent that allows highly specific and effective downstream targeting of AR in PSA-expressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating PCa.
Competing Interest Statement
Disclosure of potential conflicts of interest. H.L., S.-E.S. and D.U. are listed as coinventors on several patents regarding the humanized and/or murine forms of 5A10, which are owned by Diaprost. HL, DLJT, SES and DU are consultants/advisory board members and have stock in Diaprost AB. H.L. holds ownership interest (including patents) in OPKO Health, and reports other remuneration from OPKO Health. S.M.L. reports receiving commercial research grants from Regeneron and Telix, holds ownership interest (including patents) in Voreyda, Imaginab, and Elucida, and is a consultant/advisory board member for Johnson and Johnson. Memorial Sloan Kettering Cancer Center has filed for IP protection for inventions related to α-particle technology of which M.R.M. is an inventor. M.R.M. was a consultant for Actinium Pharmaceuticals, Regeneron, Progenics, Bridge Medicines, and General Electric.