Chimeric antigen receptor comprising BCMA nanobody linked to a chimeric intracellular signaling domain
Inventors
COMRIE, William A. • Hao, Wenshan
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12263221-B2
Publication Date
2025-04-01
Expiration Date
Abstract
The present application relates to functionally improved third generation BCMA-CARs comprising modified intracellular co-stimulatory domains, which can be used in adoptive cell therapy, e.g., in treatment of diseases and disorders such as cancer.
Core Innovation
The invention relates to a chimeric antigen receptor that binds B cell maturation antigen (BCMA) and comprises an extracellular domain comprising the amino acid sequence of SEQ ID NO: 8, a transmembrane domain, and a chimeric intracellular domain. The chimeric intracellular domain consists of a first, a second and at least a third signal transduction domain including an ICOS intracellular domain as set forth in SEQ ID NO: 2, a truncated CD137 (4-1BB) intracellular domain as set forth in SEQ ID NO: 3, and a truncated CD3ζ domain as set forth in SEQ ID NO: 4.
The disclosed BCMA-CAR comprises the amino acid sequence as set forth in SEQ ID NO: 5, with extracellular sequence information identified as SEQ ID NO: 1 and a full-length CAR sequence described as SEQ ID NO: 5. The constructs are characterized as third-generation BCMA-targeting CARs featuring a BCMA-binding nanobody extracellular domain combined with a chimeric intracellular signaling module.
The disclosure addresses the tradeoff between durability and reduced surface expression in prior 2nd/3rd generation CARs. The disclosed constructs are described as improving CAR surface expression while also reducing cytokine production including IL-2, TNFα, and IFNγ, lowering PD-1 expression and adverse phenotypic events, and maintaining function over repeated stimulations.
Claims Coverage
The independent claim is directed to a BCMA-specific chimeric antigen receptor with a defined extracellular BCMA-binding domain and a three-part chimeric intracellular signaling domain. The independent claim includes three inventive features.
BCMA-binding extracellular domain with SEQ ID NO: 8
An extracellular domain comprising the amino acid sequence of SEQ ID NO: 8.
Three-part chimeric intracellular signaling domain
A chimeric intracellular domain comprising a first, a second and at least a third signal transduction domain, wherein the first signal transduction domain consists of an ICOS intracellular domain as set forth in SEQ ID NO: 2; the second signal transduction domain consists of a truncated CD137 (4-1BB) intracellular domain as set forth in SEQ ID NO: 3; and the at least third signal transduction domain consists of a truncated CD3ζ domain as set forth in SEQ ID NO: 4.
BCMA-CAR amino acid sequence as set forth in SEQ ID NO: 5
Wherein the BCMA-CAR comprises the amino acid sequence as set forth in SEQ ID NO: 5.
Overall, the claim coverage centers on a BCMA-CAR defined by a specific BCMA-binding extracellular domain (SEQ ID NO: 8), a chimeric intracellular signaling arrangement using ICOS (SEQ ID NO: 2), truncated CD137/4-1BB (SEQ ID NO: 3), and truncated CD3ζ (SEQ ID NO: 4), and a specified full-length CAR amino acid sequence (SEQ ID NO: 5).
Stated Advantages
Improves CAR surface expression.
Reduces cytokine production including IL-2, TNFα, and IFNγ.
Lower PD-1 expression and adverse phenotypic events.
Maintains function over repeated stimulations.
Provides comparable in vitro tumor killing to leading clinical BCMA CARs with a superior safety profile.
Long-term co-culture shows improved efficacy with dose-dependent tumor burden reduction and improved survival in a xenograft mouse model.
Documented Applications
Therapeutic use for multiple myeloma and BCMA+ cancers using the disclosed BCMA-CAR constructs.
In vitro tumor killing comparisons against leading clinical BCMA CARs described in the disclosure.
Xenograft mouse model using a Gaussia luciferase xenograft model to show efficacy including dose-dependent tumor burden reduction and improved survival.
Interested in licensing this patent?