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Publication Number
US-11891426-B2
Publication Date
2024-02-06
Expiration Date
Abstract
CD19 variants, methods of identifying CD19 variants, and methods of using such CD19 variants, e.g., for treating cancer, are described.
Core Innovation
CD19 variants are disclosed as polypeptides having at least 99% sequence identity to SEQ ID NO:2 and amino acid substitutions at positions 62/64/66. The variants are identified by screening variant libraries for improved binding to anti-CD19 antibodies and/or increased resistance to protease cleavage and/or increased thermal stability versus SEQ ID NO:2.
The disclosed stable CD19 variants are defined relative to maintaining extracellular CD19 structural integrity for efficacy in a cancer immunotherapy context. The document links variant engineering to restored or improved antibody binding, protease resistance, and thermal stress tolerance while maintaining the SEQ ID NO:2 anchored framework.
The disclosure also describes CD19 variant compositions, including fusion proteins comprising an antibody/scaffold polypeptide and a CD19 variant, and nucleic acids and vectors encoding the CD19 variants. Cellular therapeutics are described in connection with CAR T cells using these CD19 variants.
Claims Coverage
The independent claim coverage centers on CD19 variants having at least 99% sequence identity to SEQ ID NO:2 with amino acid substitutions at positions 62/64/66. The claims provide three inventive features: improved binding to an anti-CD19 antibody, increased resistance to protease cleavage, and, in some disclosures, increased thermal stability.
CD19 variant with high identity to SEQ ID NO:2
A CD19 variant having at least 99% sequence identity to SEQ ID NO:2.
Amino acid substitutions at positions 62/64/66 selected from specified sets
The CD19 variant comprises amino acid substitutions at positions 62/64/66 of the amino acid sequence of SEQ ID NO:2 selected from the specified substitution sets.
Improved binding to an anti-CD19 antibody
The CD19 variant has improved binding to an anti-CD19 antibody relative to a polypeptide comprising the amino acid sequence of SEQ ID NO:2.
More resistance to protease cleavage
The CD19 variant is more resistant to protease cleavage relative to a polypeptide comprising the amino acid sequence of SEQ ID NO:2.
Overall, the claim coverage is directed to CD19 variants anchored to SEQ ID NO:2 with substitutions at positions 62/64/66, where selected substitution sets are tied to improved anti-CD19 antibody binding, increased resistance to protease cleavage, or increased thermal stability.
Stated Advantages
Improved binding to an anti-CD19 antibody relative to a polypeptide comprising the amino acid sequence of SEQ ID NO:2.
More resistance to protease cleavage relative to a polypeptide comprising the amino acid sequence of SEQ ID NO:2.
Increased thermal stability versus SEQ ID NO:2.
Documented Applications
Cellular therapeutics in a CAR T-cell context using CD19 variant fusion proteins and/or CD19 variants encoded by nucleic acids and vectors.
CD19 variant compositions including fusion proteins comprising an antibody/scaffold polypeptide and a CD19 variant.
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