IP Library Granted Patent US 11,959,118
Granted Patent B2
US 11,959,118 · App. 17/075,343 · Granted Apr 16, 2024

Fc-containing polypeptides having improved properties and comprising mutations at positions 243 and 264 of the Fc-region

Inventors: Terrance A. Stadheim (Lyme, NH); Dongxin Zha (Houston, TX); Liming Liu (Ambler, PA)
Assignee: Merck Sharp & Dohme LLC
C12P21/005C07K16/00C07K16/241C07K16/2863C07K16/32C07K16/40A61K2039/505C07K2317/14C07K2317/41C07K2317/51C07K2317/515C07K2317/52C07K2317/71C07K2317/732C07K2317/734
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Quick Facts
Patent No.
US 11,959,118
App. No.
17/075,343
Granted
Apr 16, 2024
Kind
B2
Abstract

The present invention is directed to methods and compositions for the production of Fc-containing polypeptides having improved properties and comprising mutations at positions 243 and 264 of the Fc region.

Claims (19)

1. A method for increasing the bioavailability of an Fc-containing polypeptide when administered subcutaneously, comprising:

introducing mutations at amino acid positions 243 and 264 of the Fc region of an Fc-containing polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 18, wherein the mutation at position 243 is selected from the group consisting of: F243A, F243 G, F243 S, F243 T, F243V, F243L, F243I, F243D, F243Y, F243E, F243R, F243W, and F243K and the mutation at position 264 is selected from the group consisting of: V264A, V264G, V264S, V264T, V264D, V264E, V264K, V264W, V264H, V264P, V264N, V264Q and V264L,

wherein the numbering is according to the EU index as in Kabat; and

wherein the bioavailability of the Fc-containing polypeptide comprising the mutations is increased when the Fc-containing polypeptide is administered subcutaneously compared to subcutaneous administration of an Fc-containing polypeptide without said mutations.

2. The method of claim 1 , wherein the mutations are F243A and V264A.

3. The method of claim 1 , wherein the Fc-containing polypeptide is produced in a genetically modified host cell that has been genetically engineered to produce an Fc-containing polypeptide having sialylated N-glycans.

4. The method of claim 1 , wherein the Fc-containing polypeptide is an antibody.

5. The method of claim 1 , wherein the Fc-containing polypeptide comprises sialylated N-glycans.

6. The method of claim 3 , wherein the sialic acid residues in the sialylated N-glycans are attached via α-2,6 linkages.

7. The method of claim 1 , wherein the Fc-containing polypeptide has one or more of the following properties when compared to a parent Fc-containing polypeptide: reduced effector function, increased anti-inflammatory properties, increased sialylation, and reduced binding to FcγRI, FcγRIIa, FcγRIIb and FcγRIIIa.

8. A method for producing an Fc-containing polypeptide having increased bioavailability when administered subcutaneously, comprising:

(a) providing a host cell comprising a nucleic acid molecule encoding an Fc-containing polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 18 and having alanine at positions 243 and 264 of the Fc, wherein the host cell has been genetically engineered to produce glycoproteins having sialylated N-glycans in which the sialic acid residues in the sialylated N-glycans are attached via α-2,6 linkages, and wherein the Fc numbering is according to the EU index as in Kabat;

(b) culturing the transformed host cell under conditions that induce expression of the nucleic acid molecule encoding the Fc-containing polypeptide to produce an Fc-containing polypeptide comprising sialylated N-glycans in which the sialic acid residues in the sialylated N-glycans are attached via α-2,6 linkages; and

(c) isolating the Fc-containing polypeptide comprising the sialylated N-glycans in which the sialic acid residues in the sialylated N-glycans are attached via α-2,6 linkages from the transformed host cell to produce the Fc-containing polypeptide having increased bioavailability when administered subcutaneously compared to subcutaneous administration of an Fc-containing polypeptide without said mutations.

9. The method of claim 8 , wherein the host cell is a yeast host cell.

10. The method of claim 9 , where the yeast host cell is Pichia pastoris.

11. The method of claim 8 , wherein the Fc-containing polypeptide is an antibody.

12. The method of claim 8 , wherein the Fc-containing polypeptide comprises sialylated N-glycans.

13. The method of claim 12 , wherein the sialic acid residues in the sialylated N-glycans are attached via α-2,6 linkages.

Assignments (2)
MERGER Recorded Aug 8, 2022
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 061102/0145 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 20, 2020
From: STADHEIM, TERRANCE A.; ZHA, DONGXING; LIU, LIMING
To: MERCK SHARP & DOHME CORP.
Reel/Frame 054113/0387 →