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Publication Number
US-11771718-B2
Publication Date
2023-10-03
Expiration Date
Abstract
Disclosed herein are methods and compositions including antigen-binding polypeptides comprising a stalk region and a stalk extension region. In some cases, the antigen-binding compositions comprising the stalk extension region has increased expression on a cell surface and, in some cases, has increased antigen-binding efficiency. A subject antigen binding polypeptide can be a chimeric antigen receptor (CAR).
Core Innovation
The disclosure relates to chimeric polypeptides comprising an antigen-binding region, a transmembrane region, and a spacer region connecting the transmembrane region with the antigen binding region. The spacer region comprises a stalk region comprising about 20 to about 60 amino acids and at least one dimerization site, and one to five stalk extension regions, wherein each stalk extension region comprises fewer dimerization sites than the stalk region.
The chimeric polypeptides are described in terms of how stalk and stalk extension regions affect properties associated with engineered immune effector polypeptides. Adding stalk extension regions can increase cell-surface expression and/or antigen-binding efficiency, and is associated with improved functional activity, including cytotoxicity and cytokine-related measures such as IFNγ and TNF.
The engineered molecules and their use in engineered T cells and related cell types are also described. Constructs are described in the context of chimeric antigen receptors and engineered T cell receptors, including engineered CAR-T cells and NK cells, and methods are described for increasing expansion of engineered T cells by engineering a nucleic acid encoding the chimeric polypeptide to comprise a stalk extension domain.
Claims Coverage
The independent claims comprise 2 core claim groups: a structural chimeric polypeptide claim and a method claim for increasing expansion of an engineered T cell. Across these claims, the inventive features center on the relative dimerization-site architecture of the stalk versus stalk extension regions and the resulting engineering of immune effector cells and their expansion.
Spacer architecture with fewer dimerization sites in stalk extensions
A chimeric polypeptide comprising an antigen-binding region, a transmembrane region, and a spacer region connecting the transmembrane region with the antigen binding region, wherein the spacer region comprises a stalk region comprising about 20 to about 60 amino acids and at least one dimerization site and one to five stalk extension regions, wherein each stalk extension region comprises fewer dimerization sites than the stalk region.
Increasing engineered T cell expansion via nucleic acid encoding a stalk extension domain
A method of increasing expansion of an engineered T cell expressing a chimeric polypeptide comprising engineering a nucleic acid encoding the chimeric polypeptide to comprise a stalk extension domain, thereby generating an engineered T cell.
Overall, the independent claims cover chimeric polypeptides defined by a stalk-and-extension spacer region in which stalk extension regions have fewer dimerization sites than the stalk region, and a method of increasing expansion of an engineered T cell by engineering a nucleic acid to encode the chimeric polypeptide with a stalk extension domain.
Stated Advantages
Increased expression on a cell surface compared to an otherwise identical polypeptide that lacks a stalk extension region.
Improved cytotoxicity compared with a cell expressing an otherwise identical antigen-binding polypeptide that lacks the stalk extension region.
Improved functional activity, including cytotoxicity and cytokine release such as IFNγ and TNF.
Increased expansion of an engineered T cell.
Documented Applications
Engineered T cells expressing the described chimeric polypeptides, including engineered CAR-T cells, are used in a context associated with increased expansion and improved functional activity.
Engineered NK cells expressing the described chimeric polypeptides are described in the disclosure context.
Therapeutic targeting of broad antigen examples is documented, including CD19, CD33, BCMA, EGFRvIII, and other listed antigens/receptors, in a therapeutic dosing/administration context [procedural detail omitted for safety].
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