Novel Bispecific Monoclonal Antibody Demonstrates Preclinical Promise Against STEAP1 Target in mCRPC

The novel immunotherapy AMG 509 has demonstrated promising preclinical activity in STEAP1-expressing prostate cancer cells. Results of the ongoing first-in-human study of AMG 509 in patients with metastatic castration-resistant prostate cancer (mCRPC) are anticipated.

In a presentation during the 27th Annual Prostate Cancer Foundation Scientific Retreat, W. Kevin Kelly, DO, explained the potential of this novel agent and its development progress.

“In the preclinical studies, AMG 509 shows potent tumor progression in vitro and in vivo. We are currently building AMG 509 in a phase 1 first-in-human study in patients with relapsed or refractory metastatic CRPC. This study is now open and recruiting patients,” said Kelly, director of the Division of Solid Tumor Oncology in the Department of Medical Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, and associate director of translational research at the Sidney Kimmel Cancer Center in Philadelphia, Pennsylvania.

Preclinical Promise

AMG 509 is a bispecific monoclonal antibody (mAb), specifically a bispecific XmAb 2 + 1, directed against six transmembrane epithelial antigen of the prostate 1 (STEAP1)–expressing cells. The agent consists of an anti-CD3 single chain variable fragment that binds T cells, 2 humanized anti-STEAP1 Fab domains, and an effectorless Fc domain to extend the half-life, and was designed to redirect T-effector cells to kill STEAP1-expressing cells.

STEAP1 is detected at elevated levels in about 88% of mCRPC samples by immunohistochemistry (IHC) and also at low levels in normal prostate cells, making it an exciting target in prostate cancer. “STEAP1 is truly a prostate-specific target,” Kelly commented.

AMG 509 works by simultaneously binding to CD3-positive T cells and STEAP1-positive cancer cells, at which point the agent triggers CD3 clustering at the surface of T cells as well as T-cell–mediated redirected lysis of the STEAP1-positive cancer cells.

“By binding to the surface STEAP1 on tumor cells and surface CD3 on T cells, AMT 509 redirects a patient’s T cells to attack and eradicate cancer cells,” Kelly explained. “The payload here is the patient’s own T cells. Importantly, AMG 509 triggers activation and proliferation of the patient’s own T cells, which are certainly capable of killing cancer cells.”

In vitro, AMG 509 demonstrated potent and selective T-cell–mediated destruction of STEAP-1-expressing cancer cells in both prostate cancer and Ewing sarcoma cancer cell lines.

Kelly noted that AMG 509 had greater activity in cell lines with higher levels of STEAP1. Approximately 84% of primary prostate tumors express levels of STEAP1 that would be sufficient for AMG 509 activity, which was considered to be above 62 fragments/kilobase/million on RNA sequencing. Metastatic lesions were found to express higher STEAP1 levels even than primary tumors.

In a 22RV1 cell prostate xenograft model, treatment with AMG 509 led to increased T-cell infiltration. Responses were seen even at doses as low as 0.1 mg/kg.

Moving Into Human Trials

An open-label phase 1 study was initiated in January 2020 to assess the potential of AMG 509 in patients with mCRPC (NCT04221542); the trial is currently enrolling patients.

The study consists of a dose-exploration and a dose-expansion phase with 40 patients expected to be enrolled in the first phase and 30 in the second. In the dose-exploration phase, the investigators are looking to determine the maximum tolerated dose and recommended phase 2 dose for AMG 509. In the expansion phase, the primary outcomes are the safety and tolerability of the agent. Second outcome measures include pharmacokinetic parameters, objective response rate, prostate-specific antigen response, overall survival, and circulating tumor cell response.

Patient eligibility criteria consist of confirmed mCRPC that is refractory to novel hormonal therapies and disease that has failed 1 to 2 prior taxane regimens or the patient is not suited for taxane therapy. Additionally, patients are required to have adequate hematologic, renal, hepatic, and cardiac function. Those with disease requiring immunosuppressive therapy, untreated central nervous system or leptomeningeal disease, or small cell or neuroendocrine carcinoma of the prostate are excluded from the trial.

Reference:

Kelly WK, Danila DC, Edenfield WJ, et al. Phase 1 study of AMG 509, a STEAP1 x CD3 T cell–recruiting XmAb 2+1 immune therapy, in patients with metastatic castration resistant prostate cancer (mCRPC). Presented at: 27th Annual Prostate Cancer Foundation