Phase I Trials of Anti-ENPP3 Antibody–Drug Conjugates in Advanced Refractory Renal Cell Carcinomas

Abstract

To determine the safety, pharmacokinetics, and recommended phase II dose of an antibody-drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC). Two phase I studies were conducted sequentially with 2 ADCs considered equivalent, hybridoma-derived AGS-16M8F and Chinese hamster ovary-derived AGS-16C3F. AGS-16M8F was administered intravenously every 3 weeks at 5 dose levels ranging from 0.6 to 4.8 mg/kg until unacceptable toxicity or progression. The study was terminated before reaching the MTD. A second study with AGS-16C3F started with the AGS-16M8F bridging dose of 4.8 mg/kg given every 3 weeks. The AGS-16M8F study ( = 26) closed before reaching the MTD. The median duration of treatment was 12 weeks (1.7-83 weeks). One subject had durable partial response (PR; 83 weeks) and 1 subject had prolonged stable disease (48 weeks). In the AGS-16C3F study ( = 34), the protocol-defined MTD was 3.6 mg/kg, but this was not tolerated in multiple doses. Reversible keratopathy was dose limiting and required multiple dose deescalations. The 1.8 mg/kg dose was determined to be safe and was associated with clinically relevant signs of antitumor response. Three of 13 subjects at 1.8 mg/kg had durable PRs (range, 100-143 weeks). Eight subjects at 2.7 mg/kg and 1.8 mg/kg had disease control >37 weeks (37.5-141 weeks). AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks. .

Impaired Expression of Ectonucleotidases in Ectopic and Eutopic Endometrial Tissue Is in Favor of ATP Accumulation in the Tissue Microenvironment in Endometriosis

“…It might well be a new target for pharmacological therapy of endometriosis. Indeed, targeting NPP3 is feasible since phase 1 trials using an antibody drug conjugate targeting this protein have been completed in patients with advanced metastatic renal cell carcinoma with promising antitumor results [36].…”

Advances in Antibody–Drug Conjugate Design: Current Clinical Landscape and Future Innovations

“…Nevertheless, the payload is still under clinical evaluation in earlier phases, as the payload for GSK2857916 and AGS-16C3F. [65][66][67] Several other auristatin payloads, currently under clinical evaluation, with DAR values ranging from 2 to 15, have been developed to overcome some limitations of the cathepsine B-sensitive mc-vc-PABC-MMAE payload. These agents are:…”

Potential New Therapeutic Approaches for Renal Cell Carcinoma

“…During the phase I trial for the drug, a portion of the patients experienced partial response or stable disease beyond 100 weeks and 37 weeks, respectively, indicating that the therapy may benefit a subset of patients. 58 Targeted therapy with oncolytic viruses is also a promising direction. Pexastimogene devacirepvec is a modified vaccinia virus that is able to selectively target tumor cells via a thymidine kinase gene inactivation.…”