BAFF-R targeted chimeric antigen receptor-modified T-cells and uses thereof
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Publication Number
US-12215162-B2
Publication Date
2025-02-04
Expiration Date
Abstract
Provided herein are T cells expressing a chimeric antigen receptor (CAR) targeted to B cell activating factor receptor (BAFF-R). The CAR targeted to BAFF-R (BAFF-R CAR) described herein includes a domain that binds BAFF-R. Methods of making and using the BAFF-R CAR are also provided.
Core Innovation
The invention relates to nucleic acid molecules encoding chimeric antigen receptors targeted to BAFF-R (B cell activating factor receptor). The chimeric antigen receptor includes an scFv directed to BAFF-R, where the scFv comprises a light chain variable region and a heavy chain variable region with defined CDR L1, CDR L2, CDR L3 and CDR H1, CDR H2, CDR H3.
The BAFF-R targeted chimeric antigen receptor further includes a CD4 transmembrane domain or variant thereof, a costimulatory domain comprising a 4-1BB costimulatory domain or variant thereof, and a CD3ζ signaling domain or variant thereof, with 1-5 amino acid modifications described for the domain variants. The invention also relates to humanized/chimeric antibodies targeting BAFF-R for anti-inflammatory and therapeutic purposes.
The documented embodiments include engineering BAFF-R CAR-T cells using the specified scFv and signaling architecture, with BAFF-R-specific cytotoxicity and functional activity. The description further reports inhibition of BAFF/BAFF-R interaction, limited internalization in the antibody context, persistence upon rechallenge, and in vivo xenograft evidence for tumor growth retardation or eradication and long-term tumor-free survival, including drug-resistant models and comparison to CD19 CAR-T in CD19-resistant contexts.
Claims Coverage
The independent claim coverage centers on a BAFF-R-targeted CAR nucleic acid encoding an scFv with specified CDR sequences and a modular CAR architecture. Across the items, four inventive features are described, with dependent claims also referring to delivery into human T cells and narrowed cancer indications.
BaFF-r targeted scFv defined by CDR L1/l2/l3 and CDR H1/h2/h3
A nucleic acid molecule encoding a chimeric antigen receptor wherein the scFv is targeted to BAFF-R and includes a light chain variable region and a heavy chain variable region defined by CDR L1, CDR L2, CDR L3, and CDR H1, CDR H2, CDR H3.
Cd4 transmembrane domain with limited amino-acid modifications
A CD4 transmembrane domain or variant thereof having 1-5 amino acid modifications.
4-1bb costimulatory domain with limited amino-acid modifications
A costimulatory domain comprising a 4-1BB costimulatory domain or variant thereof having 1-5 amino acid modifications.
Cd3ζ signaling domain with limited amino-acid modifications
A CD3ζ signaling domain or variant thereof having 1-5 amino acid modifications.
Overall, the claim coverage centers on BAFF-R-targeted CAR nucleic acid molecules defined by specific scFv CDR sequences and a modular CAR design using a CD4 transmembrane domain, a 4-1BB costimulatory domain, and a CD3ζ signaling domain, each permitting 1-5 amino acid modifications.
Stated Advantages
Induction of tumor growth retardation or eradication and long-term tumor-free survival in described in vivo xenograft evidence.
BAFF-R-specific cytotoxicity and functional activity.
Persistence upon rechallenge.
ADCC-dependent cytotoxicity activity in the BAFF-R antibody context, with no CDC described.
Activity described as resistance-supporting in a CD19-resistant model context using BAFF-R CAR-T.
Documented Applications
Treatment or indication for lymphoma subtypes including mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, and Burkitt's lymphoma.
Treatment or indication for leukemia subtypes and multiple myeloma.
Autoimmune diseases.
Anti-inflammatory and therapeutic purposes.
Engineering BAFF-R CAR-T cells.
Transduced human T cells.
Specified cancer indications, including lymphoma indications.
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