	US 12,403,180 B2
	Interleukin-18 variants and methods of use
Aaron Ring, New Haven, CT (US); Ting Zhou, New Haven, CT (US); and Suzanne Fischer, New Haven, CT (US)
Assigned to YALE UNIVERSITY, New Haven, CT (US)
Filed by YALE UNIVERSITY, New Haven, CT (US)
Filed on Mar. 8, 2023, as Appl. No. 18/180,389.
Application 18/180,389 is a continuation of application No. 16/123,063, filed on Sep. 6, 2018.
Claims priority of provisional application 62/652,279, filed on Apr. 3, 2018.
Claims priority of provisional application 62/554,605, filed on Sep. 6, 2017.
Prior Publication US 2023/0355714 A1, Nov. 9, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 38/20 (2006.01); A61K 35/17 (2025.01); A61K 47/64 (2017.01); A61P 35/00 (2006.01); C07K 14/54 (2006.01); A61K 35/768 (2015.01); A61K 38/17 (2006.01); C07K 14/705 (2006.01); C12N 15/85 (2006.01)

CPC A61K 38/20 (2013.01) [C07K 14/54 (2013.01); A61K 35/17 (2013.01); A61K 35/768 (2013.01); A61K 38/1774 (2013.01); A61K 47/642 (2017.08); A61K 2300/00 (2013.01); A61P 35/00 (2018.01); C07K 14/70596 (2013.01); C07K 2319/02 (2013.01); C07K 2319/21 (2013.01); C07K 2319/35 (2013.01); C07K 2319/50 (2013.01); C12N 15/85 (2013.01)]

3 Claims

1. A method comprising administering to a subject:

(a) a polynucleic acid encoding an IL-18 variant polypeptide, wherein the IL-18 variant polypeptide comprises 90% or more sequence identity with WT IL-18 as set forth in SEQ ID NO:30 and five or more substitution mutations, relative to wildtype IL-18 as set forth in SEQ ID NO:30, selected from the group consisting of: Y1, L5, K8, M51, K53, S55, Q56, P57, G59, M60, E77, Q103, S105, D110, N111, M113, V153, and N155 and specifically binds to IL-18 receptor (IL-18R) and exhibits decreased binding affinity to IL-18 binding protein (IL-18BP) relative to the wild-type IL-18; and

(b) a cell that is an immune cell or an engineered immune cell, wherein the IL-18 variant polypeptide comprises substitution mutations, relative to wild-type IL-18 as set forth in SEQ ID NO:30, at positions:

(i) M51, M60, S105, D110, and N111;

(ii) M51, S55, G59, M60, S105, D110, N111, and V153;

(iii) Y1, M51, M60, S105, D110, and N111;

(iv) Y1, M51, K53, M60, S105, D110, and N111;

(v) K8, M51, S55, G59, M60, S105, D110, and N155;

(vi) K8, M51, S55, G59, M60, S105, D110, N111, and V153;

(vii) L5, M51, K53, M60, S105, D110, and V153;

(viii) L5, M51, S55, G59, M60, S105, D110, N111, and N155;

(ix) L5, M51, S55, M60, Q103, S105, D110, N111, and V153;

(x) L5, M51, S55, M60, S105, D110, N111, V153, and N155;

(xi) L5, M51, S55, G59, M60, S105, D110, N111, V153, and N155;

(xii) L5, K8, M51, S55, M60, S105, N111, V153, and N155;

(xiii) L5, K8, M51, K53, M60, S105, D110, N111, and N155;

(xiv) Y1, L5, M51, K53, M60, S105, D110, and N155;

(XV) Y1, M51, K53, G59, M60, S105, D110, N111, V153, and N155;

(xvi) Y1, K8, M51, K53, M60, Q103, S105, D110, N111, and N155;

(xvii) Y1, K8, M51, M60, S105, D110, and N111;

(xviii) Y1, L5, M51, K53, M60, Q103, S105, D110, and N111;

(xix) Y1, K8, M51, K53, G59, M60, Q103, S105, D110, N111, V153, and N155;

(xx) Y1, K8, M51, K53, G59, M60, S105, D110, N111, and N155;

(xxi) Y1, K8, M51, G59, M60, Q103, S105, D110, N111, V153, and N155;

(xxii) Y1, L5, M51, G59, M60, E77, S105, D110, and N111;

(xxiii) M51, Q56, P57, M60, Q103, S105, D110, N111, and M113;

(xxiv) M51, Q56, P57, M60, Q103, S105, D110, and M113;

(XXV) M51, K53, Q56, P57, M60, D110, and N111;

(xxvi) M51, K53, Q56, P57, M60, Q103, S105, D110, N111, and M113;

(xxvii) M51, K53, Q56, M60, Q103, S105, D110, N111, and M113;

(xxviii) M51, K53, Q56, P57, Q103, S105, D110, N111, and M113;

(xxix) M51, K53, Q56, P57, M60, S105, D110, and N111;

(xxx) M51, K53, Q56, P57, M60, Q103, D110, N111, and M113;

(xxxi) M51, Q56, P57, M60, Q103, D110, N111, and M113; or

(xxxii) M51, K53, Q56, S105, D110, and N111.