Il-2 based constructs
AssigneeOrionis Biosciences BV
InventorsNikolai KLEY, Erik DEPLA, Lennart ZABEAU, Anje CAUWELS
Life of this patent
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Abstract
The present invention relates, in part, to chimeric proteins or chimeric protein complexes, such as Fc-based chimeric protein complexes, comprising interleukin 2, or a variant thereof, and their use as therapeutic agents.
Claims162
A chimeric protein or protein complex comprising:
- (a) a modified IL-2 signaling agent, wherein the modified IL-2 signaling agent has one or more mutations or modifications relative to a wild type signaling agent having SEQ ID NO:
- 1 that confer improved safety and reduced affinity or bioactivity of the modified IL-2 signaling agent for IL-2Rαβγ and/or IL-2Rβ and/or IL-2Rγ and/or IL-2Rα, relative to the wild type IL-2 signaling agent;
- and
- (b) one or more targeting moieties, said targeting moieties comprising recognition domains which specifically bind to antigens or receptors of interest,
- wherein the modified IL-2, and the one or more targeting moieties are optionally connected with one or more linkers,
- wherein the modified IL-2 signaling agent comprises:
- (i) a mutation selected from D20E, D20F, D20G, D20H, D20I, D20K, D20L, and D20V;
- or
- (ii) a mutation selected from N88G, N88E, N88K, N88Q, and N88V;
- or
- (iii) a mutation selected from Q126G, Q126A, Q126E, Q126F, Q126H, Q126I, Q126K, Q126L, Q126N, Q126P, Q126R, Q126S, Q126T, Q126V, Q126W, and Q126Y;
- or
- (iv) a mutation selected from (i) and (iii) or a mutation selected from (ii) and (iii);
- or
- (v) one or more mutations selected from:
- R38A/F42K/N88G/C125A,
- F42K/C125A,
- D20E/C125A,
- D20F/C125A,
- D20G/C125A,
- D20H/C125A,
- D20I/C125A,
- D20K/C125A,
- D20L/C125A,
- D20N/C125A,
- D20S/C125A,
- D20T/C125A,
- D20V/C125A,
- N88A/C125A,
- N88D/C125A,
- N88G/C125A,
- N88E/C125A,
- N88H/C125A,
- N88I/C125A,
- N88K/C125A,
- N88Q/C125A,
- N88R/C125A,
- N88T/C125A,
- N88V/C125A,
- D20E/R38A/F42K,
- D20E/R38A/F42K/C125A,
- D20V/R38A/F42K,
- D20V/R38A/F42K/C125A,
- R38A/F42Y/E62A/C125A,
- R38A/F42Y/Y45A/E62A,
- F42Y/Y45A/L72G,
- R38A/F42Y/Y45A/E62A/C125A,
- F42Y/Y45A/L72G/C125A,
- R38A/F42K/N88G,
- R38A/F42K/Q126G,
- R38A/F42K/Q126I,
- R38A/F42K/Q126Y,
- R38A/F42K/Q126G/C125A,
- R38A/F42K/Q1261/C125A,
- R38A/F42K/Q126Y/C125A,
- R38A/F42K/E62A/N88G, and
- R38A/F42K/E62A/N88G/C125A.
A chimeric protein or protein complex comprising:
- (a) a modified IL-2 signaling agent, wherein the modified IL-2 signaling agent has one or more mutations or modifications relative to a wild type signaling agent having SEQ ID NO:
- 1 that confer improved safety and reduced affinity or bioactivity of the modified IL-2 signaling agent for IL-2Rαβγ and/or IL-2Rβ and/or IL-2Rγ and/or IL-2Rα, relative to the wild type IL-2 signaling agent;
- and
- (b) one or more targeting moieties, said targeting moieties comprising recognition domains which specifically bind to antigens or receptors of interest,
- wherein the modified IL-2, and the one or more targeting moieties are optionally connected with one or more linkers,
- wherein the modified IL-2 signaling agent comprises a glycosylation mutation, wherein the mutation decreases or eliminates glycosylation of the modified IL-2 signaling agent.
A chimeric protein or protein complex comprising:
- (a) a modified IL-2 signaling agent, wherein the modified IL-2 signaling agent has one or more mutations or modifications relative to a neoleukin signaling agent having SEQ ID NO:
- 2 that confer improved safety and reduced affinity or bioactivity of the modified IL-2 signaling agent for IL-2Rαβγ and/or IL-2Rβ and/or IL-2Rγ and/or IL-2Rα, relative to the neoleukin signaling agent;
- and
- (b) one or more targeting moieties, said targeting moieties comprising recognition domains which specifically bind to antigens or receptors of interest,
- wherein the modified IL-2 signaling agent, and the one or more targeting moieties are optionally connected with one or more linkers,
- wherein the modified IL-2 signaling agent comprises one or more mutations at a position selected from D15 and N40, optionally wherein the mutation is selected from D15T, D15H, N401, N40G, and N40R.
The chimeric protein or protein complex of any one of the above claims, wherein the one or more targeting moieties are directed against a tumor cell, endothelial cell, epithelial cell, mesenchymal cell, tumor stroma or stromal cell, and/or ECM.
The chimeric protein or protein complex of any one of the above claims, wherein the one or more targeting moieties are directed against an immune cell and/or organ cells, and/or tissue cells.
The chimeric protein or protein complex of any one of the above claims, wherein the targeting moiety comprises a recognition domain that is a full-length antibody, a single-domain antibody, a recombinant heavy-chain-only antibody (VHH), a single-chain antibody (scFv), a shark heavy-chain-only antibody (VNAR), a microprotein (e.g. cysteine knot protein, knottin), a darpin, an anticalin, an adnectin, an aptamer, a Fv, a Fab, a Fab′, a F(ab′)2, a peptide mimetic molecule, a natural ligand for a receptor, or a synthetic molecule.
The chimeric protein or protein complex of any one of the above claims, wherein the recognition domain is a single-domain antibody.
The chimeric protein or protein complex of any one of the above claims, wherein the recognition domain is a VHH or humanized VHH.
The chimeric protein or protein complex of any one of the above claims, wherein the recognition domain functionally modulates the antigen or receptor of interest.
The chimeric protein or protein complex of any one of the above claims, wherein the recognition domain binds but does not functionally modulate the antigen or receptor of interest.
The chimeric protein or protein complex of any one of the above claims, comprising two or more targeting moieties.
The chimeric protein or protein complex of any one of the above claims, wherein the targeting moieties binds to one or more of the following targets:
- CD8, CTLA4, CD3, CD4, DNAM-1, Nrp1 (neurophilin), TNFR1, TNFR2, GITR, ICOS, CD20, CD70, Clec9a, NKp46, PD-1, PD-L1, PD-L2, SIRP1a, FAP, XCR1, tenascin, or ECM proteins.
The chimeric protein or protein complex of any one of the above claims, further comprising one or more additional modified signaling agents.
The chimeric protein or protein complex of any one of the above claims, wherein the chimeric protein comprises two signaling agents and one targeting moiety or two targeting moieties and one signaling agent or two of both.
The chimeric protein or protein complex of any one of the above claims, wherein the chimeric protein comprises three signaling agents or three targeting moieties or three of both.
The chimeric protein or protein complex of any one of the above claims, wherein the chimeric protein is suitable for use in a patient having one or more of:
- cancer, infections, immune disorders, autoimmune diseases, cardiovascular diseases, wound, ischemia-related diseases, neurodegenerative diseases, and/or metabolic diseases.
A recombinant nucleic acid composition encoding one or more chimeric proteins or protein complexes of any one of the above claims.
A Fc-based chimeric protein complex comprising:
- (a) a modified IL-2 signaling agent, wherein the modified IL-2 signaling agent has one or more mutations or modifications relative to a wild type signaling agent having SEQ ID NO:
- 1 that confer improved safety and reduced affinity or bioactivity of the modified IL-2 signaling agent for IL-2Rαβγ and/or IL-2Rβ and/or IL-2Rγ and/or IL-2Rα, relative to the wild type IL-2 signaling agent;
- and
- (b) one or more targeting moieties, said targeting moieties comprising recognition domains which specifically bind to antigens or receptors of interest;
- and
- (c) a Fc domain, the Fc domain optionally having one or more mutations that reduces or eliminates one or more effector functions of the Fc domain, promotes Fc chain pairing in the Fc domain, and/or stabilizes a hinge region in the Fc domain,
- wherein the modified IL-2 signaling agent comprises:
- (i) a mutation selected from D20E, D20F, D20G, D20H, D20I, D20K, D20L, and D20V;
- or
- (ii) a mutation selected from N88G, N88E, N88K, N88Q, and N88V;
- or
- (iii) a mutation selected from Q126G, Q126A, Q126E, Q126F, Q126H, Q126I, Q126K, Q126L, Q126N, Q126P, Q126R, Q126S, Q126T, Q126V, Q126W, and Q126Y;
- or
- (iv) a mutation selected from (i) and (iii) or a mutation selected from (ii) and (iii);
- or
- (v) one or more mutations selected from:
- R38A/F42K/N88G/C125A,
- F42K/C125A,
- D20E/C125A,
- D20F/C125A,
- D20G/C125A,
- D20H/C125A,
- D20I/C125A,
- D20K/C125A,
- D20L/C125A,
- D20N/C125A,
- D20S/C125A,
- D20T/C125A,
- D20V/C125A,
- N88A/C125A,
- N88D/C125A,
- N88G/C125A,
- N88E/C125A,
- N88H/C125A,
- N88I/C125A,
- N88K/C125A,
- N88Q/C125A,
- N88R/C125A,
- N88T/C125A,
- N88V/C125A,
- D20E/R38A/F42K,
- D20E/R38A/F42K/C125A,
- D20V/R38A/F42K,
- D20V/R38A/F42K/C125A,
- R38A/F42Y/E62A/C125A,
- R38A/F42Y/Y45A/E62A,
- F42Y/Y45A/L72G,
- R38A/F42Y/Y45A/E62A/C125A,
- F42Y/Y45A/L72G/C125A,
- R38A/F42K/N88G,
- R38A/F42K/Q126G,
- R38A/F42K/Q126I,
- R38A/F42K/Q126Y,
- R38A/F42K/Q126G/C125A,
- R38A/F42K/Q1261/C125A,
- R38A/F42K/Q126Y/C125A,
- R38A/F42K/E62A/N88G, and
- R38A/F42K/E62A/N88G/C125A.
A Fc-based chimeric protein complex comprising:
- (a) a modified IL-2 signaling agent, wherein the modified IL-2 signaling agent has one or more mutations or modifications relative to a wild type signaling agent having SEQ ID NO:
- 1 that confer improved safety and reduced affinity or bioactivity of the modified IL-2 signaling agent for IL-2Rαβγ and/or IL-2Rβ and/or IL-2Rγ and/or IL-2Rα, relative to the wild type IL-2 signaling agent;
- and
- (b) one or more targeting moieties, said targeting moieties comprising recognition domains which specifically bind to antigens or receptors of interest;
- and
- (c) a Fc domain, the Fc domain optionally having one or more mutations that reduces or eliminates one or more effector functions of the Fc domain, promotes Fc chain pairing in the Fc domain, and/or stabilizes a hinge region in the Fc domain,
- wherein the modified IL-2 signaling agent comprises a glycosylation mutation, wherein the mutation decreases or eliminates glycosylation of the modified IL-2 signaling agent.
A Fc-based chimeric protein complex comprising:
- (a) a modified IL-2 signaling agent, wherein the modified IL-2 signaling agent has one or more mutations or modifications relative to a neoleukin signaling agent having SEQ ID NO:
- 2 that confer improved safety and reduced affinity or bioactivity of the modified IL-2 signaling agent for IL-2Rαβγ and/or IL-2Rβ and/or IL-2Rγ and/or IL-2Rα, relative to the neoleukin signaling agent;
- and
- (b) one or more targeting moieties, said targeting moieties comprising recognition domains which specifically bind to antigens or receptors of interest,
- wherein the modified IL-2 signaling agent, and the one or more targeting moieties are optionally connected with one or more linkers,
- wherein the modified IL-2 signaling agent comprises one or more mutations at a position selected from D15 and N40, optionally wherein the mutation is selected from D15T, D15H, N401, N40G, and N40R.
A chimeric protein or protein complex comprising:
- (a) a modified IL-2 signaling agent, wherein the modified IL-2 signaling agent has a single mutation relative to a wild type signaling agent having SEQ ID NO:
- 1 that confers improved safety and reduced affinity or bioactivity of the modified IL-2 signaling agent for IL-2Rβ, relative to the wild type IL-2 signaling agent;
- and
- (b) one or more targeting moieties, said targeting moieties comprising recognition domains which specifically bind to antigens or receptors of interest,
- wherein the modified IL-2, and the one or more targeting moieties are optionally connected with one or more linkers,
- wherein the single mutation is selected from D20E, D20F, D20G, D20H, D20I, D20K, D20L, D20N, D20V, N88G, N88E, N88I, N88K, N88Q, N88R and N88V, and
- wherein the modified IL-2 signaling agent does not comprise a mutation that confers reduced affinity or bioactivity for IL-2Rα.
A Fc-based chimeric protein complex comprising:
- (a) a modified IL-2 signaling agent, wherein the modified IL-2 signaling agent has a single mutation relative to a wild type signaling agent having SEQ ID NO:
- 1 that confers improved safety and reduced affinity or bioactivity of the modified IL-2 signaling agent for IL-2Rβ, relative to the wild type IL-2 signaling agent;
- and
- (b) one or more targeting moieties, said targeting moieties comprising recognition domains which specifically bind to antigens or receptors of interest;
- and
- (c) a Fc domain, the Fc domain optionally having one or more mutations that reduces or eliminates one or more effector functions of the Fc domain, promotes Fc chain pairing in the Fc domain, and/or stabilizes a hinge region in the Fc domain,
- wherein the single mutation is selected from D20E, D20F, D20G, D20H, D20I, D20K, D20L, D20N, D20V, N88G, N88E, N88I, N88K, N88Q, N88R and N88V, and
- wherein the modified IL-2 signaling agent does not comprise a mutation that confers reduced affinity or bioactivity for IL-2Rα.
Dependencies are inferred from the claim text.