Background: ATRC-101 is a fully human, engineered IgG1 version of an antibody discovered through a target-agnostic process designed to identify patient-derived, tumor-targeting antibodies. The parental antibody of ATRC-101 was discovered from a patient with metastatic non-small cell lung cancer (NSCLC) undergoing an active immune response while receiving a checkpoint inhibitor. ATRC-101 binds selectively to human tumor specimens, including a majority of NSCLC, acral melanoma, breast, colorectal, and ovarian cancer samples. The target of ATRC-101 appears to be a tumor-associated ribonucleoprotein complex containing a form of polyadenylate-binding protein 1 (PABP-1) that can be found on the surface of tumor cells. Studies to further elucidate the tumor selectivity of ATRC-101 and the extracellular presentation of the target are ongoing. Preclinical data suggest that ATRC-101 stimulates an adaptive immune response against tumors via the innate immune system. ATRC-101 displays dose-dependent, single-agent activity in syngeneic mouse tumor models, including the EMT6 breast cancer model, which displays a T cell-excluded microenvironment and in which PD-1/PD-L1 inhibitors exhibit limited activity. ATRC-101 plus an anti-PD-1 antibody demonstrated significantly greater antitumor activity and longer survival in the EMT6 model compared with either agent alone, consistent with the mechanism of action proposed for ATRC-101. Methods: ATRC-101-A01 is an open-label, 3+3, dose-escalation phase 1b safety study of ATRC-101 as monotherapy (mono) or in combination (combo) with pembrolizumab (pembro) to treat patients with certain solid tumor types. Expansion cohorts of ≤12 patients may be enrolled at doses and frequencies at which biological activity is observed. The primary objective is to determine the safety of ATRC-101. Secondary objectives include evaluation of the following: recommended dose and schedule of ATRC-101 for expansion, pharmacokinetic profile of ATRC-101, immunogenicity, antitumor activity by RECIST v1.1, and lymphocytic infiltration in the tumor microenvironment. ATRC-101 is administered every 2 (q2w) or 3 (q3w) weeks up to 24 months or until disease progression. ATRC-101 dosing is increasing from the initial 0.3 mg/kg according to the following schedule, pending dose-limiting toxicity data: 1, 3, 10, and 30 mg/kg. In the combo cohort, ATRC-101 will be given q3w, and pembro will be administered at 200 mg q3w or 400 mg q6w to patients with disease progression while receiving prior pembro treatment or those with stable disease who were deemed by their physician to potentially benefit from the addition of ATRC-101. The q3w mono cohort is currently accruing patients at the 10-mg/kg dose, and the combo and q2w cohorts will begin at an ATRC-101 dose one level below the most recent cleared q3w mono dose. Trial registration NCT04244552. The study was approved by the institutional review board of each participating site.

Citation Format: Jonathan E. Benjamin, Nicholas Higgins, Carl Millward, Jeff DeFalco, Amy Manning-Bog, Iraz T. Aydin, Danhui Zhang, Shaun M. Lippow, Alexander Scholz, Yvonne Leung, Yanhong Zhu, Anna Sedello, Zane Rogers, Ish K. Dhawan, Daniel Emerling, William H. Robinson, Tito A. Serafini, Norman M. Greenberg. First-in-human phase 1b study of ATRC-101, a patient-derived antibody with a tumor-specific target, as monotherapy or in combination with pembrolizumab, in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT203.