Cell therapies for type 1 diabetes
AssigneeAbata Therapeutics, Inc.
InventorsGeetha MYLVAGANAM, Devapregasan MOODLEY, Jeremy BURNS, Yanbo ZHANG, Timothy NELSON
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Abstract
The present disclosure is directed to T cell receptors targeting GAD65 and isolated cell populations comprising regulatory T cells exogenously expressing said TCRs used to treat Type 1 Diabetes.
Claims55
A T cell receptor (TCR) that binds to a GAD65 peptide complexed with a major histocompatibility complex (MHC) molecule, wherein the TCR comprises an alpha chain and a beta chain, and wherein the TCR comprises:
- a CDR1-alpha sequence comprising the amino acid sequence of SEQ ID NO:
- 61,
- a CDR2-alpha sequence comprising the amino acid sequence of SEQ ID NO:
- 62,
- a CDR3-alpha sequence comprising the amino acid sequence of SEQ ID NO:
- 63,
- a CDR1-beta sequence comprising the amino acid sequence of SEQ ID NO:
- 66,
- a CDR2-beta sequence comprising the amino acid sequence of SEQ ID NO:
- 67, and/or
- a CDR3-beta sequence comprising the amino acid sequence of SEQ ID NO:
- 68.
A T cell receptor (TCR) that binds to a GAD65 peptide complexed with a major histocompatibility complex (MHC) molecule, wherein the TCR comprises an alpha chain and a beta chain, and wherein the TCR comprises:
- a CDR1-alpha sequence comprising the amino acid sequence of SEQ ID NO:
- 110,
- a CDR2-alpha sequence comprising the amino acid sequence of SEQ ID NO:
- 111,
- a CDR3-alpha sequence comprising the amino acid sequence of SEQ ID NO:
- 112,
- a CDR1-beta sequence comprising the amino acid sequence of SEQ ID NO:
- 115,
- a CDR2-beta sequence comprising the amino acid sequence of SEQ ID NO:
- 116, and/or
- a CDR3-beta sequence comprising the amino acid sequence of SEQ ID NO:
- 117.
A T cell receptor (TCR) that binds to a GAD65 peptide complexed with a major histocompatibility complex (MHC) molecule, wherein the TCR comprises an alpha chain and a beta chain, and wherein the TCR comprises:
- a CDR1-alpha sequence comprising the amino acid sequence of SEQ ID NO:
- 130,
- a CDR2-alpha sequence comprising the amino acid sequence of SEQ ID NO:
- 131,
- a CDR3-alpha sequence comprising the amino acid sequence of SEQ ID NO:
- 132,
- a CDR1-beta sequence comprising the amino acid sequence of SEQ ID NO:
- 135,
- a CDR2-beta sequence comprising the amino acid sequence of SEQ ID NO:
- 136, and/or
- a CDR3-beta sequence comprising the amino acid sequence of SEQ ID NO:
- 137.
The TCR of any one of the preceding claims, wherein the GAD65 peptide is a GAD65 555-567 peptide comprising the amino acid sequence of NFFRMVISNPAAT (SEQ ID NO:
- 109).
The TCR of any one of the preceding claims, wherein the MHC comprises HLA-DRB1*04:01.
The TCR of any one of the preceding claims, wherein the TCR is encoded as a single polypeptide, optionally wherein the polypeptide comprises an N-terminal beta domain and a C-terminal alpha domain.
The TCR of any one of the preceding claims, wherein the alpha chain comprises an alpha constant region comprising an amino acid sequence having at least 90%, 95%, or 100% identity to the amino acid sequence of SEQ ID NO:
- 106.
The TCR of any one of the preceding claims, wherein the beta chain comprises a beta constant region comprising an amino acid sequence having at least 90%, 95%, or 100% identity to the amino acid sequence of SEQ ID NO:
- 107 or 108.
The TCR of any one of the preceding claims, wherein TCR comprises one or more amino acid substitutions to cysteine residues in the alpha chain constant region and the beta chain constant region, and wherein the cysteine residues are capable of forming one or more disulfide bridges.
The TCR of any one of the preceding claims, wherein the alpha chain constant region comprises a T48C amino acid substitution relative to an alpha chain constant region comprising the amino acid sequence of SEQ ID NO:
- 106, and wherein the beta chain constant region comprises a S57C amino acid substitution relative to a beta chain constant region comprising the amino acid sequence of SEQ ID NO:
- 108.
An engineered nucleic acid encoding the TCR of any one of the preceding claims.
An engineered cell comprising a TCR that specifically binds GAD65 555-567 complexed with a major histocompatibility complex (MHC) molecule, wherein the TCR is exogenous to the engineered cell.
An engineered regulatory T cell comprising a TCR that specifically binds GAD65 555-567 peptide, complexed with a major histocompatibility complex (MHC) molecule, wherein the TCR is exogenous to the engineered cell.
Dependencies are inferred from the claim text.