NZ795140B2 - Polypeptide variants and uses thereof - Google Patents

Abstract

Discloses amino acid substitutions increasing effector function of a polypeptide comprising a human Igg1 Fc region, methods of increasing effector function by introducing these substitutions, variants themselves, compositions comprising the variants and their use for treating cancer. In particular substitutions K439E and S440K

Claims (21)

1. A method of increasing complement-dependent cytotoxicity (CDC) specificity of a combination of at least a first and a second parent ptide, wherein the at least first and second parent polypeptide each comprises an Fc-domain of an immunoglobulin and a binding region, n said method comprises (i) introducing to the at least first parent polypeptide a K439E mutation in the Fc region of a human IgG1 heavy chain numbered according to the EU index in a human IgG1; and (ii) introducing to the at least second parent polypeptide a S440K mutation in the Fc-region of a human IgG1 heavy chain numbered according to the EU index in a human IgG1.

2. The method according to claim 1, n the at least first and second parent polypeptides are antibodies.

3. The method according to claim 2, wherein the antibodies are monospecific, bispecific or multispecific.

4. The method ing to any one of claims 1 to 3, wherein said method comprises introducing a mutation in both the first and second parent polypeptides.

5. The method according to any one of the claims 1 to 4, wherein the effector function is increased when the antibody is bound to its antigen.

6. The method according to claim 5, wherein the antigen is on an antigenexpressing cell, cell membrane, or virion.

7. Use of (i) a first preparation comprising a first parent polypeptide modified ing to the method of any one of claims 1 to 6 and a second preparation comprising a second parent ptide modified according to the method of any one of claims 1 to 6, or 20956410_1 (GHMatters) P38333NZ06 (ii) a preparation comprising a combination of at least a first parent polypeptide and a second parent polypeptide modified according to the method of any one of claims 1 to 6; in the manufacture of a medicament for treating cancer or a bacterial, viral or fungal infection via ng an effector response, in the presence of human complement or an effector cell, against a cell, cell membrane, or virion expressing a target to which one or more parent polypeptides comprising an Fc-domain of an immunoglobulin and a binding region bind.

8. The use according to claim 7, wherein the effector response is complement dependent cytotoxicity (CDC), an Fc-mediated effector response selected from an Fcmediated effector response ed from C1q-binding, complement activation, complement ent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxity , FcRn-binding, Fc-receptor binding including Fc-gamma orbinding , n A- binding, Protein G-binding, antibody-dependent cellular phagocytosis (ADCP), complement-dependent cellular cytotoxicity (CDCC), ment-enhanced cytotoxicity, opsonisation, Fc-containing polypeptide internalization, target downmodulation, ADC uptake, induction of apoptosis, cell death, cell cycle arrest, and any combination thereof.

9. The use according to claim 7 or 8, wherein the mutation in the position corresponding to K439 in the Fc-region of human IgG1 heavy chain is K439E, and the mutation in the position corresponding to S440 in the Fc-region of human IgG1 heavy chain is S440K.

10. The method according to any one of claims 1 to 6 or use according to any one of claims 7 to 9, wherein the parent antibody or the combination of a first parent dy and a second parent polypeptide(s) is/are a human IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgD or IgE.

11. The method or use according to claim 10, wherein the parent antibody or the combination of a first parent dy and a second parent polypeptide(s) is/are a human full-length dy. 20956410_1 ters) P38333NZ06

12. At least one composition comprising a first variant of a parent polypeptide and a second variant of a parent polypeptide, wherein the first variant comprises a first in of an immunoglobulin and a binding region, wherein the second variant comprises a second Fc-domain of an immunoglobulin and a binding region, and wherein (i) said first variant comprises a K439E mutation in the Fc-region of a human IgG1 heavy chain, and (ii) said second variant comprises a S440K mutation in the Fc-region of a human IgG1 heavy chain.

13. The at least one composition ing to claim 12, wherein a first composition comprises said first variant of a parent polypeptide and a second composition comprises said second variant of a parent polypeptide.

14. The at least one composition ing to claim 12 or 13, wherein said variant or variants is/are antibodies.

15. The at least one composition according to any one of claims 12 to 14, wherein said first and the second variant bind different epitopes on the same antigen, or on ent antigens.

16. The at least one composition according to any one of claims 12 to 15, wherein one or both of said first variant and second variant is/are conjugated to a drug, toxin or abel.

17. The at least one composition according to any one of claims 12 to 16, wherein one or both of said first t and second variant is/are part of a fusion protein.

18. The at least one composition according to any one of claims 12 to 17 and a pharmaceutically able carrier.

19. A kit-of-parts comprising the at least one composition as defined in any one of claims 12 to 18 for simultaneous, separate or sequential use in therapy. 20956410_1 (GHMatters) P38333NZ06

20. The use of the at least one composition according to any one of claims 12 to 18 or kit-of-parts according to claim 19, in the manufacture of a medicament for treating ; or treating a bacterial, viral or fungal infection, via inducing an effector response against a cell, cell membrane or virion expressing a target.

21. A method according to any one of claims 1 to 6 or 10 to 11, the use according to any one of claims 7 to 11 or 20, the at least one composition ing to any one of claims 12 to 18, or a kit according to claim 19, substantially as hereinbefore described. 20956410_1 (GHMatters) P38333NZ06