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US 12,594,325 B2Granted
Interleukin-18 variants and methods of use
AssigneeYale University
InventorsAaron Ring, Ting Zhou, Suzanne Fischer
Life of this patent
Estimating the term…
Abstract
The present invention provides compositions and methods comprising an activator of interleukin-18 (IL-18) activity for use in therapeutic and non-therapeutic applications. The activator provides IL-18 signaling activity even in the presence of an inhibitory molecule 5 such as IL-18 binding protein (IL-18BP).
Claims17
An immune cell comprising a nucleic acid encoding an interleukin 18 (IL-18) variant polypeptide that specifically binds to IL-18 receptor (IL-18R) and exhibits decreased binding affinity to IL-18 binding protein (IL-18BP) relative to wild-type IL-18 and a chimeric antigen receptor (CAR) or a T-cell receptor, wherein the IL-18 variant polypeptide comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs:
- 34-59, 73-91, 191, 192, or 193.
A composition comprising:
- a polynucleic acid encoding an interleukin 18 (IL-18) variant polypeptide, wherein the IL-18 variant polypeptide comprises 90% or more sequence identity with wild-type (WT) IL-18 as set forth in SEQ ID NO:30 and specifically binds to IL-18 receptor (IL-18R) and exhibits decreased binding affinity to IL-18 binding protein (IL-18BP) relative to the WT IL-18;
- and
- a cell that is an immune cell, wherein the IL-18 variant polypeptide comprises substitution mutations, relative to WT IL-18 as set forth in SEQ ID NO:30, at positions comprising:
- (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.
33 more elements
An immune cell comprising:
- a polynucleic acid encoding an interleukin 18 (IL-18) variant polypeptide, wherein the IL-18 variant polypeptide comprises 90% or more sequence identity with wildtype (WT) IL-18 as set forth in SEQ ID NO:30 and specifically binds to IL-18 receptor (IL-18R) and exhibits decreased binding affinity to IL-18 binding protein (IL-18BP) relative to the WT IL-18, wherein the IL-18 variant polypeptide comprises substitution mutations, relative to WT IL-18 as set forth in SEQ ID NO:30, at positions comprising:
- (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.
31 more elements
Dependencies are inferred from the claim text.