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US 2024/0392008 A1Published application
Multispecific proteins binding to nkp46, a cytokine receptor, a tumour antigen and cd16a
OwnerLaurent GAUTHIER, Yannis MOREL +1inventors
InventorsLaurent GAUTHIER, Yannis MOREL, Olivier DEMARIA
Life of this patent
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Abstract
Multispecific proteins that bind NKp46 and specifically redirect effector cells to lyse a target cell of interest via multiple receptors are provided. The proteins have utility in the treatment of disease, notably cancer or infectious disease.
Claims22
1-45. (canceled)
A multispecific protein comprising:
- an antigen binding domain (ABD) that binds to an antigen of interest;
- an ABD that binds to a human NKp46 polypeptide;
- an Fc domain dimer capable of binding FcRn, optionally wherein the Fc domain dimer is further capable of binding to CD16A;
- and an ABD that binds a human cytokine receptor present on NK cells;
- wherein
- (i) the multispecific protein comprises polypeptide chains 1, 2 and 3:
- (ii) Va-1, Vb-1, Va-2 and Vb-2 are each a VH domain or a VL domain, wherein one of Va-1 and Vb-1 is a VH and the other is a VL and wherein Va-1 and Vb-1 form a first antigen binding domain (ABD), wherein one of Va-2 and Vb-2 is a VH and the other is a VL and wherein Va-2 and Vb-2 form a second ABD, wherein the first ABD binds the antigen of interest and the second ABD binds NKp46;
- (iii) CH1 is a heavy chain constant domain 1 and CL is a light chain constant domain;
- one of (CH1 or CL)a and (CH1 or CL)b is a CH1 and the other is a CL such that a (CH1/CL) pair is formed;
- (iv) the hinge is an immunoglobulin hinge region or portion thereof;
- (v) L1, L2 and L3 are each an amino acid domain linker, wherein L1, L2 and L3 can be different or the same;
- (vi) CH2 and CH3 are human immunoglobulin CH2 and CH3 domains, respectively;
- and
- (vii) Cyt is an ABD that binds a human cytokine receptor present on NK cells, optionally wherein Cyt is a cytokine polypeptide or portion thereof that binds to a cytokine receptor present on NK cells, wherein Cyt is a wild-type or variant human IL-2, IL-15, IL-21, IL-7, IL-27, IL-12, IL-18, IFN-α or IFN-β polypeptide.
11 more elements
A multispecific protein comprising:
- an antigen binding domain (ABD) that binds to an antigen of interest;
- an ABD that binds to a human NKp46 polypeptide;
- an Fc domain dimer capable of binding FcRn, optionally wherein the Fc domain dimer is further capable of binding to CD16A;
- and an ABD that binds a human cytokine receptor present on NK cells;
- wherein
- (i) the multispecific protein comprises polypeptide chains 1, 2 and 3:
- (ii) Va-1, Vb-1, Va-2 and Vb-2 are each a VH domain or a VL domain, wherein one of Va-1 and Vb-1 is a VH and the other is a VL and wherein Va-1 and Vb-1 form a first antigen binding domain (ABD), wherein one of Va-2 and Vb-2 is a VH and the other is a VL and wherein Va-2 and Vb-2 form a second ABD, wherein the first ABD binds NKp46 and the second ABD binds the antigen of interest;
- (iii) CH1 is a heavy chain constant domain 1 and CL is a light chain constant domain;
- one of (CH1 or CL)a and (CH1 or CL)b is a CH1 and the other is a CL such that a (CH1/CL) pair is formed;
- (iv) the hinge is an immunoglobulin hinge region or portion thereof;
- (v) L1, L2 and L3 are each an amino acid domain linker, wherein L1, L2 and L3 can be different or the same;
- (vi) CH2 and CH3 are human immunoglobulin CH2 and CH3 domains, respectively;
- and
- (vii) Cyt is an ABD that binds a human cytokine receptor present on NK cells, optionally wherein Cyt is a cytokine polypeptide or portion thereof that binds to a cytokine receptor present on NK cells, wherein Cyt is a wild-type or variant human IL-2, IL-15, IL-21, IL-7, IL-27, IL-12, IL-18, IFN-α or IFN-β polypeptide.
11 more elements
A multispecific protein comprising:
- an antigen binding domain (ABD) that binds to an antigen of interest;
- an ABD that binds to a human NKp46 polypeptide;
- an Fc domain dimer capable of binding FcRn, optionally wherein the Fc domain dimer is further capable of binding to CD16A;
- and an ABD that binds a human cytokine receptor present on NK cells, wherein
- (i) the multispecific protein comprises a polypeptide chains 1, 2, 3 and 4 wherein:
- (ii) Va-1, Vb-1, Va-2 and Vb-2 are each a VH domain or a VL domain, wherein one of Va-1 and Vb-1 is a VH and the other is a VL and wherein Va-1 and Vb-1 form a first antigen binding domain (ABD), wherein one of Va-2 and Vb-2 is a VH and the other is a VL and wherein Va-2 and Vb-2 form a second ABD, wherein the first ABD binds the antigen of interest and the second ABD binds NKp46;
- (iii) CH1 is a heavy chain constant domain 1 and CL is a light chain constant domain;
- one of (CH1 or CL)a and (CH1 or CL)c is a CH1 and the other is a CL such that a (CH1/CL) pair is formed;
- (iv) one of (CH1 or CL)b and (CH1 or CL)d is a CH1 and the other is a CL such that a (CH1/CL) pair is formed;
- (v) the hinge is an immunoglobulin hinge region or portion thereof;
- (vi) L1, L2 and L3 are each an amino acid domain linker, wherein L1, L2 and L3 can be different or the same;
- (vii) CH2 and CH3 are human immunoglobulin CH2 and CH3 domains, respectively;
- and
- Cyt is an ABD that binds a human cytokine receptor present on NK cells, optionally wherein
- (viii) Cyt is a cytokine polypeptide or portion thereof that binds to a cytokine receptor present on NK cells, wherein Cyt is a wild-type or variant human IL-2, IL-15, IL-21, IL-7, IL-27, IL-12, IL-18, IFN-α or IFN-β polypeptide.
12 more elements
A multispecific protein capable of potentiating NK cell cytotoxicity toward a target cell expressing an antigen of interest, the multispecific protein comprising:
- (a) an antigen binding domain (ABD) that binds to the antigen of interest;
- (b) an ABD that binds to a human NKp46 polypeptide;
- (c) an Fc domain dimer capable of binding FcRn, optionally wherein the Fc domain dimer is further capable of binding to CD16A;
- and
- (d) an ABD that binds a human cytokine receptor present on NK cells, wherein the ABD Is a wild-type or variant human IL-2, IL-15, IL-21, IL-7, IL-27, IL-12, IL-18, IFN-α or IFN-β polypeptide;
- wherein the ABD that binds to a human NKp46 polypeptide is connected at its C-terminus to the N-terminus of Fc domain, optionally via an Ig-derived or non-Ig-derived polypeptide linker, and the Fc domain is connected at its C-terminus to the N-terminus of the ABD that binds a human cytokine receptor via a polypeptide linker, and wherein the protein has a single ABD that binds to a human NKp46 polypeptide and a single ABD that binds a human cytokine receptor such that the protein exhibits monovalent binding to each of NKp46 and the human cytokine receptor.
3 more elements
Dependencies are inferred from the claim text.