High affinity PD-1 agents and methods of use
AssigneeThe Board of Trustees of the Leland Stanford Junior University
InventorsAaron Michael Ring, Andrew Kruse, Aashish Manglik, Irving L. Weissman, Roy Louis Maute, Melissa N. McCracken, Sydney Gordon
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Abstract
High affinity PD-1 mimic polypeptides are provided, which (i) comprise at least one amino acid change relative to a wild-type PD-1 protein; and (ii) have an increased affinity for PD-L1 relative to the wild-type protein. Compositions and methods are provided for modulating the activity of immune cells in a mammal by administering a therapeutic dose of a pharmaceutical composition comprising a high affinity PD-1 mimic polypeptide, which blocks the physiological binding interaction between PD-1 and its ligand PD-L1 and/or PD-L2.
Claims30
A high affinity programmed cell death 1 (PD-1) mimic polypeptide, comprising an amino acid sequence that is a variant of a human wild-type PD-1 ectodomain sequence, wherein the high affinity PD-1 mimic polypeptide:
- (a) lacks a wild-type PD-1 transmembrane domain,
- (b) comprises an amino acid sequence having 85% or more sequence identity to the amino acid sequence set forth in any of SEQ ID NOs:
- 2-25 and 39-46, and
- (c) relative to the amino sequence set forth in SEQ ID NO:
- 2, comprises one or more amino acid changes that cause an increased affinity for human and/or mouse programmed cell death 1 ligand 1 (PD-L1).
A high affinity programmed cell death 1 (PD-1) mimic polypeptide, comprising an amino acid sequence that is a variant of a human wild-type PD-1 ectodomain sequence, wherein the high affinity PD-1 mimic polypeptide:
- (a) lacks a wild-type PD-1 transmembrane domain;
- and
- (b) comprises the amino acid sequence set forth in any of SEQ ID NOs:
- 3-25, and 39-46.
A method of treating an individual having cancer or having a chronic infection, the method comprising:
- administering to the individual, a high affinity programmed cell death 1 (PD-1) mimic polypeptide in an amount effective for reducing the binding of PD-1 on a first cell with PD-L1 on a second cell, wherein the high affinity PD-1 mimic polypeptide:
- (a) lacks a wild-type PD-1 transmembrane domain,
- (b) comprises an amino acid sequence having 85% or more sequence identity to the amino acid sequence set forth in any of SEQ ID NOs:
- 2-25 and 39-46, and
- (c) relative to the amino sequence set forth in SEQ ID NO:
- 2, comprises 5 or more amino acid changes that cause an increased affinity for human and/or mouse PD-L1, wherein the 5 or more amino acid changes are located at amino acid positions, relative to the sequence set forth in SEQ ID NO:
- 2, selected from:
- V39, L40, N41, Y43, R44, M45, S48, N49, Q50, T51, D52, K53, A56, Q63, G65, Q66, V72, H82, M83, R90, Y96, L97, A100, S102, L103, A104, P105, K106, and A107.
Dependencies are inferred from the claim text.