Rationally designed protein compositions
Inventors
Li, Chiang J. • UNNIRAMAN, SHYAM • BADER, HANNAH • Lau, Alan
Assignees
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Publication Number
US-12378295-B2
Publication Date
2025-08-05
Expiration Date
Abstract
Novel compositions and methods relating to or derived from a rationally designed fusion protein composition combines a therapeutic antibody with an IL2 mutant that can simultaneously enhance anti-tumor immunity or derepress tumor-associated immunosuppression along with direct activation of effector cells by IL2 without activating Treg are provided. The fusion protein can be used to prevent or therapeutically treat cancer.
Core Innovation
The invention relates to rationally designed fusion protein compositions that connect an entire anti-PDL1 antibody to a mutant Interleukin-2 polypeptide. The fusion connects the mutant IL2 to the anti-PDL1 antibody at the antibody heavy-chain C-terminus via a linker, including a serine-glycine linker such as SEQ ID NO:19. The anti-PDL1 component binds and blocks PD-L1/PD-1 mediated immunosuppression.
The mutant IL2 polypeptides are defined by amino acid sequence identity to SEQ ID NO:25 or SEQ ID NO:27, and related MutIL2 variants and formats are described. The fusion architecture leverages the antibody Fc to extend half-life via Fc neonatal receptor pathways. The MutIL2 component is engineered to shift IL2-driven biology toward effector activation with reduced regulatory activation.
The invention is presented as a means to derepress PD-L1/PD-1 mediated immunosuppression while simultaneously activating effector T and NK cells through a mutant IL2 design that preferentially modulates T_eff/T_reg activation ratios. The document further describes pharmaceutical composition and treatment/prophylaxis use cases for cancers expressing PD-L1, together with sequence listings and engineered architecture options.
Claims Coverage
The document provides two independent claim topics: one anti-PDL1 antibody–MutIL2 fusion protein and one mutant IL2 polypeptide. Across these claim topics, six inventive features are identified.
Entire anti-PDL1 antibody connected to a mutant IL2 polypeptide
A fusion protein comprising an entire anti-PDL1 antibody connected to a mutant IL2 polypeptide, wherein the mutant IL2 polypeptide comprises an amino acid sequence identical to SEQ ID NO: 25 or SEQ ID NO: 27.
Mutant IL2 polypeptide less selective towards a high-affinity receptor
A mutant IL2 polypeptide that is less selective towards a high-affinity receptor of a wild type IL2, wherein the mutant IL2 polypeptide comprises an amino acid sequence identical to SEQ ID NO: 25 or SEQ ID NO: 27.
Anti-PDL1 fusion linker defined as a serine-glycine linker
The fusion protein having a linker sequence that is a serine-glycine linker.
Linker sequence identical to SEQ ID NO: 19
The fusion protein having a linker sequence of SEQ ID NO: 19.
Anti-PDL1 antibody variable-region sequence pairings
An anti-PDL1 antibody whose heavy-chain variable region and light-chain variable region contain sequence pairings selected from specified SEQ ID combinations.
PDL1 binding and PD-1/PD-L1 blocking and de-repression in activated PBMCs
An anti-PDL1 antibody characterized by binding PDL1 with Kd<100 nM, blocking the PDL1–PD1 interaction in vitro, and/or reversing PDL1-mediated repression of effector T cells in activated PBMC cultures.
Overall claim coverage centers on an anti-PDL1 antibody–MutIL2 fusion protein defined by sequence identity to SEQ ID NO:25 or SEQ ID NO:27, including linker and anti-PDL1 functional criteria, and on the MutIL2 polypeptide itself being less selective toward the high-affinity IL2 receptor of wild type IL2.
Stated Advantages
Enhances anti-tumor immunity while derepressing PD-L1/PD-1-mediated immunosuppression.
Preferentially activates effector T and NK cells without activating Tregs.
Improves effector T/NK activation relative to Treg activation via altered activation ratios.
Documented Applications
Treatment and prophylaxis of cancers expressing PD-L1.
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