First-in-human phase Ib study of ATRC-101, an engineered version of a patient-derived antibody targeting a tumor-restricted ribonucleoprotein complex.

Abstract

TPS3168 Background: ATRC-101 is a fully human, engineered IgG1 version of an antibody discovered through a a target-agnostic screen to identify patient-derived antibodies that bind selectively to public tumor antigens. The parental antibody was identified from B cells in the active immune response of a patient receiving checkpoint therapy for Stage IV non-small cell lung cancer (NSCLC). A fluorescently conjugated version of ATRC-101 binds selectively to human tumor specimens including a majority of NSCLC, acral melanoma, breast, colorectal, and ovarian cancer samples. No reactivity of toxicological significance is found across a wide range of normal human tissues. 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 often observed in human tumors, and in which checkpoint inhibitors targeting the PD-1 axis exhibit limited activity. Dosing with ATRC-101 in the EMT6 model causes marked changes in the tumor microenvironment, including a shift from the M2 to the M1 macrophage phenotype and infiltration of T cells. ATRC-101 does not appear to act via NK cell-driven ADCC; instead, activity in vivo is dependent both on Fc region interactions with Fc receptors, likely on myeloid rather than lymphoid cells, and on the presence of CD8+ T cells. ATRC-101 binds to a target that is a ribonucleoprotein (RNP) complex containing polyadenylate-binding protein 1 (PABP-1) bound to poly(A)RNA. Whereas both PABP-1 and poly(A)RNA are ubiquitously expressed at high levels in normal tissues and have been localized intracellularly, the ATRC-101 target is detected extracellularly on tumor cells grown in vivo. The basis for the tumor-selectivity of ATRC-101 as well as the extracellular localization of the target is under investigation. Ascending doses of ATRC-101 were well tolerated in multiple non-clinical safety studies. Methods: ATRC-101-A01 is an open-label, 3+3, Phase 1b safety study in patients with acral melanoma, NSCLC, breast, ovarian, and colorectal cancers. Participants are accruing in the first dose cohort. ATRC-101 is administered every 21 days up to 24 months or until disease progression. The primary objective of the trial is to determine the safety and tolerability of ATRC-101. Secondary objectives are to characterize the pharmacokinetic profiles of ATRC-101 and to assess antitumor activity as determined by RECIST 1.1 and lymphocytic infiltration in the tumor microenvironment. Clinical trial information: NCT04244552 .