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Abbv-101, a Highly Potent and Selective Clinical Stage Bruton Tyrosine Kinase Degrader for the Treatment of B-Cell Malignancies
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 key 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. 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. In preclinical studies, the BTK degrader ABBV-101 has shown potent in vitro and in vivo efficacy in BCR pathway-dependent leukemia/lymphoma models, including covalent BTK inhibitor resistant BTK-C481S systemic mouse CLL and human DLBCL models. ABBV-101 degrades BTK-WT and BTK-C481S with similar sub-nanomolar potency in the human DLBCL cell line TMD8 which translates to potent cellular growth…
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NX-5948, BGB-16673 and ABBV-101 are other BTK degraders in clinical development that have shown preliminary activity in ongoing studies.
“Other BTK degraders in clinical development include NX-5948, BGB-16673 and ABBV-101, which have shown preliminary activity in ongoing studies(91–93).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [92]
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Bruton Tyrosine Kinase Degraders in B-Cell Malignancies
Huynh, T., Rodrı́guez, S., & Danilov, A. V. (2024) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-23-0520 · Cited by 4
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Metadata
- Authors
- Pan, C., Gururaja, T. L., Li, H., Nguyen, H., Zhai, Y., Xie, X., Ding, R.-X., Mathew, R., Hoh, H. Y., Jia, Z. J., Liu, B., Shu, C., Assaily, W., Lam, L. T., Riehm, J. J., Stevenson, C., Will, C., Innocenti, F., & Rivkin, A.
- Affiliations
- AbbVie (United States) (US)
- 1AbbVie Bay Area, South San Francisco, CA
- 3AbbVie Bay Area, SAN FRANCISCO, CA
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2023-11-02
- Volume
- 142
- Issue
- Supplement 1
- Pages
- 1887-1887
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W4389259210
- Cited by
- 10
- References
- 0
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- Bruton's tyrosine kinase, BTK degraders, B-cell malignancies, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, BTK C481S mutation, BTK inhibitor resistance, protein degradation, oral bioavailability, B cell receptor signaling, Eμ-TCL1 mouse model, xenograft models
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