JP-2022515331-A5 -

Dates

Publication Date

20221226

Application Date

20191218

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 activity and for regulating immune responses in organisms. [Invention 1001] a) Below: i) A peptide epitope wherein the peptide has a length of at least 4 amino acids, ii) The first major histocompatibility complex (MHC) polypeptide and The first polypeptide, including b) A second polypeptide comprising a second MHC polypeptide, and c) At least one immunomodulatory polypeptide at least one heterodimer containing A T cell regulatory polymer polypeptide, including [Invention 1002] At least one of the above at least one immunomodulatory polypeptides is a variant immunomodulatory polypeptide that exhibits a lower affinity for the allogeneic co-immunomodulatory polypeptide compared to the affinity of the corresponding wild-type immunomodulatory polypeptide for the allogeneic co-immunomodulatory polypeptide. The epitope binds to the T cell receptor (TCR) on the T cell with an affinity of at least 10⁻⁷ M , thereby, 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 the allogeneic co-immunomodulatory polypeptide and a TCR that binds to the epitope with an affinity of at least 10⁻⁷ M , The second T cell expresses the allogeneic 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, and/ or ii) The ratio of the binding affinity of a control T cell regulatory multimer polypeptide containing a wild-type immunomodulatory polypeptide to an allogeneic co-immunomodulatory polypeptide, to the binding affinity of the T cell regulatory multimer polypeptide containing a variant of the wild-type immunomodulatory polypeptide, when measured by biolayer interferometry, is in the range of 1.5:1 to 10⁶ : 1. T cell regulatory polymer polypeptide according to the present invention 1001. [Invention 1003] 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 approximately 10⁻⁴ M to approximately 10⁻⁷ M , approximately 10⁻⁴ M to approximately 10⁻⁶ M , and / or c) The ratio of the binding affinity of a control T cell regulatory multimer polypeptide containing a wild-type immunomodulatory polypeptide to an allogeneic co-immunomodulatory polypeptide, to the binding affinity of the T cell regulatory multimer polypeptide containing a variant of the wild-type immunomodulatory polypeptide, when measured by biolayer interferometry, is at least 10:1, at least 50:1, at least 10² : 1, or at least 10³ :1. T cell regulatory polymer polypeptide according to the present invention 1002. [Invention 1004] a1) The first polypeptide is arranged in order from the N-terminus to the C-terminus. i) The peptide epitope, ii) The first MHC polypeptide, and iii) at least one immunomodulatory polypeptide including and b1) The second polypeptide described above is arranged in order from the N-terminus to the C-terminus. i) The second MHC polypeptide, and ii) Immunoglobulin (Ig) Fc polypeptide including; or a2) The first polypeptide is formed in order from the N-terminus to the C-terminus, i) The peptide epitope, and ii) The first MHC polypeptide including and b2) The second polypeptide described above is arranged in order from the N-terminus to the C-terminus. i) at least one immunomodulatory polypeptide, ii) The second MHC polypeptide, and iii) Ig Fc polypeptide including; or a3) The first polypeptide is formed in order from the N-terminus to the C-terminus. i) The peptide epitope, and ii) The first MHC polypeptide including and b3) The second polypeptide is arranged in the order from the N-terminus to the C-terminus. i) The second MHC polypeptide, and ii) Ig Fc polypeptide, and iii) at least one immunomodulatory polypeptide including; or a4) The first polypeptide is arranged in order from the N-terminus to the C-terminus. i) The peptide epitope, and ii) The first MHC polypeptide including and b4) The second polypeptide is arranged in the order from the N-terminus to the C-terminus. i) The second MHC polypeptide, and ii) at least one immunomodulatory polypeptide including; or a5) The first polypeptide is formed in order from the N-terminus to the C-terminus. i) The peptide epitope, and ii) The first MHC polypeptide including and b5) The second polypeptide is arranged in order from the N-terminus to