Abstract 605: ABBV-101, a highly potent and selective clinical stage Bruton tyrosine kinase degrader, overcomes BTK mutation-induced resistance to BTK inhibitors
Authors: Pan Chin , Riehm Jacob , Gururaja Tarikere L. , Li Haiyan , Nguyen Henry , Zhai Yongjiao , Xie Xiaoping , Ding Rong-Xian , Matthew Rebecca , Hoh Hana Y. , Jia Zhaozhong J. , Liu Bo , Shu Cassandra P. , Stevenson Claudina A. , Will Christine , Innocenti Federico , Assaily Wissam , Lam Lloyd T. , Rivkin Alexey 
Published: March 2024

Abstract
Bruton tyrosine kinase (BTK), a clinically validated target for various B-cell malignancies, plays a critical role in regulating cell growth, adhesion, and homing to lymphoid tissues that provide a microenvironment favorable to cancer cells. Despite the success of approved covalent BTK inhibitors in diseases such as CLL, most patients do not achieve complete response with monotherapy and eventually relapse, often via the emergence of the BTK-C481S mutation. Although second-generation reversible BTK inhibitors may temporarily overcome the C481S mutation, novel BTK mutations associated with resistance emerged in the clinic recently. Additionally, covalent BTK inhibitors have not shown sufficient differentiation from standard-of-care (SoC) in B-cell malignancies, such as diffuse large B cell lymphoma (DLBCL) to warrant approval to date. To address these unmet needs, a next-generation orally bioavailable BTK degrader ABBV-101 has been developed. Unlike BTK inhibitors that solely bind to and impede the catalytic domain of BTK, ABBV-101 eliminates the protein in a highly selective fashion. This degradation mechanism targets both the catalytic and scaffolding functions of BTK, and thus may enable deeper and more durable responses in patients with B-cell malignancies. Cellular activity of ABBV-101 was determined in a panel of DLBCL cell lines. We show that most non-germinal center B cell DLBCL (non-GCB-DLBCL) cell lines are sensitive to ABBV-101. To determine whether ABBV-101 could overcome BTK mutations-induced resistance, we engineered human DLBCL cell line TMD8 using CRISPR technology to express these BTK mutations and tested for sensitivity to ABBV-101 and BTK inhibitors. We show that ABBV-101 demonstrates similar potent activity against all BTK mutations associated with resistance to both covalent and reversible BTK inhibitors. The modulation of downstream pathway by ABBV-101 and how it differentiates from other BTK inhibitors will be presented. Further, ABBV-101 induces complete tumor regression in the BTK-C481S TMD8 DLBCL xenograft model. A spontaneous mouse CLL model carrying BTK-C481S mutation was developed through crossing BTK-C481S knock-in mice with the Emu-TCL1 transgenic mice in the C57BL/6 background. ABBV-101 completely inhibits BTK-C481S Emu-TCL1 CLL burden increase in the blood compartment and reduces CLL burden in the spleen and lymph nodes, whereas covalent BTK inhibitors show no activity. Finally, combination with a BCL-2 inhibitor enhances the efficacy of ABBV-101 in CLL and DLBCL models. Taken together, our results suggest that ABBV-101 has potent in vitro and in vivo efficacy. ABBV-101 is currently in phase 1 clinical trial for a variety of B-cell malignancies. ClinicalTrials.gov identifier: NCT05753501
Citation Format: Chin Pan, Jacob Riehm, Tarikere L. Gururaja, Haiyan Li, Henry Nguyen, Yongjiao Zhai, Xiaoping Xie, Rong-Xian Ding, Rebecca Matthew, Hana Y. Hoh, Zhaozhong J. Jia, Bo Liu, Cassandra P. Shu, Claudina A. Stevenson, Christine Will, Federico Innocenti, Wissam Assaily, Lloyd T. Lam, Alexey Rivkin. ABBV-101, a highly potent and selective clinical stage Bruton tyrosine kinase degrader, overcomes BTK mutation-induced resistance to BTK inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 605.