667P - Phase I study to assess biodistribution of CB307, a trispecific Humabody targeting CD137, prostate-specific membrane antigen, and human serum albumin with 89Zr-CB307 PET

Background

CB307, a tri-specific Humabody targeting CD137, prostate-specific membrane antigen (PSMA), and human serum albumin, lacks an Fc domain and weighs < 50 kDa. It was designed to activate T cells exclusively in PSMA+ lesions. Preclinical studies have confirmed efficient CB307 delivery to PSMA+ tumors in mice. To understand its biodistribution, patients were imaged with PET after injection with 89-zirconium (⁸⁹Zr) labeled CB307.

Methods

Patients with PSMA-positive tumors received ⁸⁹Zr-CB307 (37 MBq / 5 mg protein) and escalating doses of unlabeled CB307 up to a maximum of 100 mg to achieve sufficient tracer in the circulation to allow tumor uptake. Subsequently, patients underwent 3 PET scans followed by a tumor biopsy (NCT05836623). Thereafter, patients entered the CB307 treatment trial (NCT04839991). Tracer uptake was measured as standardized uptake value in tumor lesions (SUV_max) and healthy tissues (SUV_mean). Blood tracer pharmacokinetics and urine tracer concentration were assessed. Tumor biopsies were stained with hematoxylin-eosin and immunohistochemically for PSMA, and autoradiography was performed. With anti-albumin magnetic beads, the % tracer bound to albumin was assessed. Tracer integrity was determined with SDS-PAGE.

Results

Five patients were enrolled. No tracer-related adverse events were reported. One patient received 5 mg ⁸⁹Zr-CB307 without unlabeled CB307, one 25 mg unlabeled CB307, and three 100 mg unlabeled CB307 with PET/CT scans at 2, 5, and 7 days (±1). The blood ⁸⁹Zr-CB307 T½ was 67.1 h at 105 mg. At 105 mg, optimal tumor-to-blood ratio (10.3) occurred on day 7, and the mean tumor lesion (n=18) SUV_max was 5.8 ± SD 2.1. ⁸⁹Zr-CB307 SUV_mean in liver was 13.7 ± SD 1.3 and spleen 3.1 ± SD 0.4, without specific uptake in lymph nodes, bone marrow, and salivary glands. Tumor biopsies showed radioactive signal. Circulating tracer was intact and ∼100% albumin-bound, urine ⁸⁹Zr-radioactivity was <2.0% of the injected dose in the 8 h post-injection, and SDS page results showed only unconjugated ⁸⁹Zr in urine.

Conclusions

CB307 targets PSMA only in tumors, without specific uptake in PSMA-positive normal tissues or lymphoid tissues.

Clinical trial identification

NCT05836623.

Editorial acknowledgement

Legal entity responsible for the study

UMCG and Crescendo Biologics Ltd.

Funding

Crescendo Biologics Ltd.

Disclosure

D.G. Knapen: Financial Interests, Institutional, Local PI: Bayer. M. Lub-de Hooge: Financial Interests, Institutional, Advisory Board: Merck; Financial Interests, Institutional, Principal Investigator: Amgen, Servier. J. Pizzey: Financial Interests, Personal, Full or part-time Employment: Crescendo Biologics Ltd. R. Williams, S. Archer, P. Bland-Ward, K. Duffy, K. Hashimoto: Financial Interests, Personal, Full or part-time Employment: Crescendo Biologics Ltd; Financial Interests, Personal, Stocks or ownership: Crescendo Biologics Ltd. D.J. de Groot: Financial Interests, Institutional, Principal Investigator: F. Hoffmann-La Roche, GE; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Local PI: Bayer. E.G.E. de Vries: Financial Interests, Institutional, Advisory Board: NSABP, Daiichi Sankyo, Crescendo Biologics Ltd; Financial Interests, Institutional, Research Grant: Amgen, Roche; Financial Interests, Institutional, Local PI: Genentech, Bayer; Financial Interests, Institutional, Principal Investigator: Servier, Regeneron, Crescendo Biologics Ltd. All other authors have declared no conflicts of interest.