A Phase 0 Study to Assess the Biodistribution and Pharmacokinetics of a Radiolabeled Antibody Targeting Human Kallikrein 2 in Participants with Metastatic Castration-Resistant Prostate Cancer

Abstract

Despite the inclusion of multiple agents within the prostate cancer treatment landscape, new treatment options are needed to address the unmet need for patients with metastatic castration-resistant prostate cancer (mCRPC). Although prostate-specific membrane antigen is the only cell-surface target to yield clinical benefit in men with advanced prostate cancer, additional targets may further advance targeted immune, cytotoxic, radiopharmaceutical, and other tumor-directed therapies for these patients. Human kallikrein 2 (hK2) is a novel prostate-specific target with little to no expression in nonprostate tissues. This first-in-human phase 0 trial uses an ¹¹¹In-radiolabeled anti-hK2 monoclonal antibody, [¹¹¹In]-DOTA-h11B6, to credential hK2 as a potential target for prostate cancer treatment. Methods: Participants with progressive mCRPC received a single infusion of 2 mg of [¹¹¹In]-DOTA-h11B6 (185 MBq of ¹¹¹In), with or without 8 mg of unlabeled h11B6 to assess antibody mass effects. Sequential imaging and serial blood samples were collected to determine [¹¹¹In]-DOTA-h11B6 biodistribution, dosimetry, serum radioactivity, and pharmacokinetics. Safety was assessed within a 2-wk follow-up period from the time of [¹¹¹In]-DOTA-h11B6 administration. Results: Twenty-two participants received [¹¹¹In]-DOTA-h11B6 and are included in this analysis. Within 6-8 d of administration, [¹¹¹In]-DOTA-h11B6 visibly accumulated in known mCRPC lesions, with limited uptake in other organs. Two treatment-emergent adverse events unrelated to treatment occurred, including tumor-related bleeding in 1 patient, which led to early study discontinuation. Serum clearance, biodistribution, and tumor targeting were independent of total antibody mass (2 or 10 mg). Conclusion: This first-in-human study demonstrates that tumor-associated hK2 can be identified and targeted using h11B6 as a platform as the h11B6 antibody selectively accumulated in mCRPC metastases with mass-independent clearance kinetics. These data support the feasibility of hK2 as a target for imaging and hK2-directed agents as potential therapies in patients with mCRPC.

Keywords: KLK2; h11B6; hK2; mCRPC.

Graphical abstract

FIGURE 1.

(A) Representative anterior and posterior whole-body images over time showing biodistribution after administration of 2 mg (top) or 10 mg (bottom) of [¹¹¹In]-DOTA-h11B6. Bars on right represent percentage of maximum pixel value over all images. (B) Average serum clearance kinetics are based on decay-corrected percentage of injected ¹¹¹In activity (percentage of injected dose per liter ± SE) across subcohort 1A (2 mg, n = 15) and subcohort 1B (10 mg, n = 6). %ID/L = percentage of injected dose per liter.

FIGURE 2.

Representative images showing tumor uptake of [¹¹¹In]-DOTA-h11B6 administered at 2 mg (top 2 images) or 10 mg (lower image). Arrows denote lesions.