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Preclinical Characterization of ARX517, a Site-Specific Stable PSMA-Targeted Antibody-Drug Conjugate for the
Lillian K Skidmore1, David Mills1, Ji Young Kim1
1Ambrx, Inc., La Jolla, California.
Abstract:
Metastatic castration-resistant prostate cancer (mCRPC) is an advanced disease in which patients ultimately fail standard-of-care androgen deprivation therapies and exhibit poor survival rates. The prostate-specific membrane antigen (PSMA) has been validated as an mCRPC tumor antigen with overexpression in tumors and low expression in healthy tissues. Using our proprietary technology for incorporating synthetic amino acids into proteins at selected sites, we have developed ARX517, an antibody-drug conjugate composed of a humanized anti-PSMA antibody site-specifically conjugated to a tubulin inhibitor at a drug-to-antibody ratio of 2. After binding PSMA, ARX517 is internalized and catabolized, leading to cytotoxic payload delivery and apoptosis. To minimize premature payload release and maximize delivery to tumor cells, ARX517 employs a noncleavable polyethylene glycol linker and stable oxime conjugation enabled via synthetic amino acid protein incorporation to ensure its overall stability. In vitro studies demonstrate that ARX517 selectively induces cytotoxicity of PSMA-expressing tumor cell lines. ARX517 exhibited a long terminal half-life and high serum exposure in mice and dose-dependent antitumor activity in both enzalutamide-sensitive and -resistant cell line-derived xenograft and patient-derived xenograft models of prostate cancer. Repeat-dose toxicokinetic studies in nonhuman primates demonstrated that ARX517 was tolerated at exposures well above therapeutic exposures in mouse pharmacology studies, indicating a wide therapeutic index. In summary, ARX517 inhibited tumor growth in diverse mCRPC models, demonstrated a tolerable safety profile in monkeys, and had a wide therapeutic index based on preclinical exposure data. Based on the encouraging preclinical data, ARX517 is currently being evaluated in a phase I clinical trial (NCT04662580).
Insights
ARX517, a novel antibody-drug conjugate targeting prostate-specific membrane antigen (PSMA), shows significant promise for treating metastatic castration-resistant prostate cancer (mCRPC). Preclinical studies demonstrate potent antitumor activity and a favorable safety profile, warranting further clinical investigation.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) presents a significant unmet need due to treatment resistance and poor survival rates.
- Prostate-specific membrane antigen (PSMA) is a validated target overexpressed in mCRPC, making it an attractive target for therapy.
- Existing therapies often fail, necessitating the development of novel treatment strategies.
Purpose of the Study:
- To evaluate the preclinical efficacy and safety of ARX517, a novel antibody-drug conjugate targeting PSMA.
- To assess the mechanism of action and therapeutic potential of ARX517 in various mCRPC models.
- To determine the safety profile and therapeutic index of ARX517 in preclinical species.
Main Methods:
- Development of ARX517 using proprietary synthetic amino acid technology for site-specific antibody-drug conjugation.
- In vitro assessment of ARX517 cytotoxicity against PSMA-expressing cancer cell lines.
- In vivo evaluation of ARX517 antitumor activity in xenograft models of prostate cancer (cell line-derived and patient-derived).
- Toxicokinetic and safety studies in nonhuman primates to determine the therapeutic index.
Main Results:
- ARX517 demonstrated selective in vitro cytotoxicity against PSMA-positive tumor cells.
- In vivo studies showed dose-dependent antitumor activity in both enzalutamide-sensitive and -resistant prostate cancer xenograft models.
- ARX517 exhibited a long terminal half-life and high serum exposure in mice.
- Nonhuman primate studies indicated ARX517 was well-tolerated at exposures significantly exceeding therapeutic levels, suggesting a wide therapeutic index.
Conclusions:
- ARX517 effectively inhibited tumor growth across diverse mCRPC preclinical models.
- The antibody-drug conjugate demonstrated a tolerable safety profile in nonhuman primates.
- Encouraging preclinical data support the ongoing clinical evaluation of ARX517 in a Phase I trial (NCT04662580).
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