JP-2022534846-A5 -

Dates

Publication Date

20230523

Application Date

20200528

Description

Summary This disclosure provides T cell regulatory polymer polypeptides (TMMPs) comprising immunomodulatory polypeptides, class I HLA polypeptides (class I HLA heavy chain polypeptides and β2 microglobulin polypeptides), and peptides that present epitopes to T cell receptors. TMMPs are useful for regulating T cell activation and for regulating immune responses in organisms. [Invention 1001] (a) (i) A peptide epitope which is a peptide having a length of at least 4 amino acids, and (ii) First major histocompatibility complex (MHC) polypeptide A first polypeptide containing, (b) A second polypeptide containing a second MHC polypeptide, (c) at least one immunomodulatory polypeptide, wherein the first and/or second polypeptide comprises the at least one immunomodulatory polypeptide, (d) an immunoglobulin (Ig) Fc polypeptide or a non-Ig scaffold, wherein the first and/or second polypeptide comprises the Ig Fc polypeptide or the non-Ig scaffold, and (e) a tumor-targeting polypeptide wherein the first and/or second polypeptide comprises the tumor-targeting polypeptide. A T cell regulatory polymeric polypeptide comprising at least one heterodimer containing [a specific compound]. [Invention 1002] The T cell regulatory multimer polypeptide of the present invention 1001, wherein at least one of the one or more immunomodulatory polypeptides is a variant immunomodulatory polypeptide that exhibits a lower affinity for the associated co-immunomodulatory polypeptide compared to the affinity of the corresponding wild-type immunomodulatory polypeptide to the associated co-immunomodulatory polypeptide. [Invention 1003] (i) The T cell regulatory polymer polypeptide binds to the first T cell with an affinity at least 25% higher than the affinity with which the T cell regulatory polymer polypeptide binds to the second T cell. The first T cell expresses on its surface a TCR that binds to the epitope with the associated co-immunomodulatory polypeptide and at least 10⁻⁷ M affinity , The second T cell expresses the associated co-immunomodulatory polypeptide on its surface, but does not express a TCR that binds to the epitope with an affinity of at least 10⁻⁷ M on its surface. so as, and/or (ii) The ratio of the binding affinity of a control T cell regulatory multimer polypeptide, including the wild-type immunomodulatory polypeptide, to the associated co-immunomodulatory polypeptide, to the binding affinity of the T cell regulatory multimer polypeptide, including the variant form of the wild-type immunomodulatory polypeptide, to the associated co-immunomodulatory polypeptide, when measured by biolayer interferometry, is in the range of 1.5:1 to 10⁶ :1. like, The T cell regulatory polymer polypeptide of the present invention 1002, wherein the epitope binds to the T cell receptor (TCR) on a T cell with an affinity of at least 10⁻⁷ M. [Invention 1004] (a) The T cell regulatory polymer polypeptide binds to the first T cell with an affinity at least 50%, at least 2 times, at least 5 times, or at least 10 times higher than the affinity it binds to the second T cell, and/or (b) The variant immunomodulatory polypeptide binds to the co-immunomodulatory polypeptide with affinity of about 10⁻⁴ M to about 10⁻⁷ M , about 10⁻⁴ M to about 10⁻⁶ M, and / or (c) The T cell regulatory multimer polypeptide of the present invention 1003, wherein the ratio of the binding affinity of a control T cell regulatory multimer polypeptide containing a wild-type immunomodulatory polypeptide to an associated co-immunomodulatory polypeptide to the binding affinity of the T cell regulatory multimer polypeptide containing a variant of the wild-type immunomodulatory polypeptide to the associated co-immunomodulatory polypeptide is at least 10:1, at least 50:1, at least 10² : 1, or at least 10³ :1 when measured by biolayer interferometry. [Invention 1005] A T cell regulatory multimer polypeptide according to any one of the present invention 1001 to 1004, wherein the second polypeptide comprises the Ig Fc polypeptide, and optionally the Ig Fc polypeptide is an IgG1 Fc polypeptide. [Invention 1006] The T cell regulatory polymer polypeptide of the present invention 1005, wherein the IgG1 Fc polypeptide comprises one or more amino acid substitutions selected from N297A, L234A, L235A, L234F, L235E, and P331S. [Invention 1007] (a5) The first polypeptide is formed in order from the N-terminus to the C-terminus. (i) The peptide epitope, (ii) The first MHC polypeptide, and (iii) comprising at least one immunomodulatory polypeptide, and (b5) The second polypeptide is arranged in order from the N-terminus to the C-terminus. (i) The second MHC polypeptide, (ii) The Ig Fc polypeptide, and (iii) comprising the tumor-targeting polypeptide, or (a1) The first polypeptide is arranged in order from the N-terminus to the C-terminus. (i) the peptide epitope, and (ii) comprising the first MHC polypeptide, (b1) The second polypeptide is arranged in order from the N-terminus to the C-terminus.