Abstract LB084: AXL as a therapeutic target in adenoid cystic carcinoma: preclinical evaluation of AXL targeting antibody-drug conjugate (ADCT-601)

Abstract

Background: Adenoid cystic carcinoma (ACC) is a rare cancer of salivary gland cancer with a significant unmet clinical need. Conventional systemic therapy has limited efficacy and there are currently no FDA approved drugs for these patients with metastatic disease. Advances in molecular profiling led identification of potential therapeutic targets, and previous studies with proteomic analysis identified AXL as a potential therapeutic target in ACC. AXL, a member of the TAM tyrosine kinase receptor family has been generally associated with poor prognosis, and its overexpression and activation is implicated in conferring resistance to conventional systemic therapies in solid tumors. ADCT-601 is an antibody drug conjugate targeting human AXL carrying novel pyrrolobenzodiazepine dimer cytotoxin as the payload. Methods: The goal of this study is to determine the in vitro and in vivo anti-tumor activity of ADCT-601 in ACC cell lines and patient-derived xenograft (ACCX) models with varying AXL expression determined by Western blot. ADCT-601 treated cell lines in vitro were analyzed by MTT-based cytotoxic assay and immunoblotting, and anti-tumorigenicity was assessed in two ACCX models. Results: ADCT-601 induced a potent dose-dependent cytotoxic effect in ACC cell lines, but its cytotoxic activity was attenuated after AXL knockdown. Biochemical data indicated that ADCT-601 treatment led to DNA damage and induction of apoptotic factors accompanied by phosphorylation of gamma-H2AX. In high AXL expressing ACCX6 model, a single dose of either 0.5 or 1.0 mg/kg ADCT-601 significantly suppressed tumor growth resulting 3/5 partial responders (PRs) at 1mg/kg and 2/5 PRs at 0.5 mg/kg, compared to the vehicle or isotype-ADC control treated mice (0/5 PR and 1/5 PR, respectively). ADCT-601 appears to eliminate tumor, as no evidence of recovery in tumor growth was observed during a 60-day period. In low AXL expressing ACCX9 model, ADCT-601 treatment (at either the 0.5 or 1.0 mg/kg dose) delayed tumor growth compared to isotype-ADC control, but did not lead to durable partial responses. Conclusion: This study demonstrated that ADCT-601 induced a potent and specific in vitro and in-vivo anti-tumor activities in AXL expressing ACC models and suggests further development of ADCT-601 in biomarker driven clinical trials. Citation Format: Joseph O. Humtsoe, Leilani Jones, Shorook Naara, Francesca Zammarchi, Nicole Spardy Burr, Patrick H. van Berkel, Patrick K. Ha, Hyunseok Kang. AXL as a therapeutic target in adenoid cystic carcinoma: preclinical evaluation of AXL targeting antibody-drug conjugate (ADCT-601) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB084.

First Use of AXL Targeting in Metastatic, Refractory, Adenoid Cystic Carcinoma: A Case Report

“…Accordingly, AXL targeting is cytotoxic in AXL-high preclinical ACC models. 13,14 Currently, there is no FDA-approved systemic therapy for ACC. 19,32,33 Despite well-documented heterogeneity, all ACCs are treated similarly, with VEGFRi and chemotherapy being the only options outside of clinical trials.…”

“…In ACC-II, AXL gene expression and protein expression are significantly increased, providing a rationale for AXL-targeted therapy. 11,13,14…”

“…In ACC-II, AXL gene expression and protein expression are significantly increased, providing a rationale for AXL-targeted therapy. 11,13,14 Mecbotamab vedotin (BA3011) is an AXL-targeting, conditionally active biologic antibody-drug conjugate that delivers the cytotoxic agent monomethyl auristatin E (MMAE). 15,16 BA3011 is designed to bind to AXL under tumor-specific conditions of accelerated glycolytic metabolism.…”

Approaches to the Management of Metastatic Adenoid Cystic Carcinoma

“…This mechanism makes the Axl pathway an interesting therapeutic target. In vitro and in vivo studies have been undertaken with ADCT-601, an antibody drug conjugate targeting AXL, which has preliminarily shown significant tumor response rates in high AXL-expressing ACC mouse models [ 106 ].…”