US2023055694A1PendingUtilityA1

Receptors providing targeted costimulation for adoptive cell therapy

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Assignee: INSTIL BIO UK LTDPriority: Jun 16, 2021Filed: Sep 28, 2022Published: Feb 23, 2023
Est. expiryJun 16, 2041(~14.9 yrs left)· nominal 20-yr term from priority
Inventors:John BridgemanRobert HawkinsRuben RodriguezGray KueberuwaMilena Kalaitsidou
A61K 2239/22A61K 2239/17A61K 40/4266A61K 40/4255A61K 40/31A61K 40/11A61K 2239/59A61K 2239/55A61K 2239/57C07K 2317/622C07K 2319/03C07K 2317/76A61K 38/00C12Y 207/10001C07K 2317/565C07K 14/70596C07K 2319/33A61P 35/00C07K 14/70521C07K 14/7051A61K 2039/505C07K 16/3007C07K 2319/02C07K 14/70578C07K 16/30C07K 14/705C07K 14/71A61K 35/17
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Claims

Abstract

Some embodiments provided herein are chimeric costimulatory antigen receptor (CoStAR), useful in adoptive cell therapy (ACT), and cells comprising the CoStAR. In some embodiments, the CoStAR can act as a modulator of cellular activity enhancing responses to defined antigens. In some embodiments, CoStAR and/or fusion proteins, nucleic acids encoding the CoStAR and therapeutic uses thereof are also provided.

Claims

exact text as granted — not AI-modified
1 - 43 . (canceled) 
     
     
         44 . A chimeric costimulatory antigen receptor (CoStAR) which comprises:
 an extracellular binding domain that binds to mesothelin (MSLN);   a transmembrane domain;   a CD28 signaling domain, wherein the CD28 signaling domain comprises the amino acid sequence of SEQ ID NO: 25; and   a CD40 signaling domain, wherein the CD40 signaling domain comprises the amino acid sequence of SEQ ID NO: 32,   wherein the extracellular binding domain comprises any one of:   (a) a HCDR1 that is an HCDR1 in SEQ ID NO: 186, a HCDR2 that is an HCDR2 in SEQ ID NO: 186, a HCDR3 that is an HCDR3 in SEQ ID NO: 186, a LCDR1 that is an LCDR1 in SEQ ID NO: 186, a LCDR2 that is an LCDR2 in SEQ ID NO: 186, and LCDR3 that is an LCDR3 in SEQ ID NO: 186;   (b) a HCDR1 that is an HCDR1 in SEQ ID NO: 187, a HCDR2 that is an HCDR2 in SEQ ID NO: 187, a HCDR3 that is an HCDR3 in SEQ ID NO: 187, a LCDR1 that is an LCDR1 in SEQ ID NO: 187, a LCDR2 that is an LCDR2 in SEQ ID NO: 187, and LCDR3 that is an LCDR3 in SEQ ID NO: 187;   (c) a HCDR1 that is an HCDR1 in SEQ ID NO: 188, a HCDR2 that is an HCDR2 in SEQ ID NO: 188, a HCDR3 that is an HCDR3 in SEQ ID NO: 188, a LCDR1 that is an LCDR1 in SEQ ID NO: 188, a LCDR2 that is an LCDR2 in SEQ ID NO: 188, and LCDR3 that is an LCDR3 in SEQ ID NO: 188;   (d) a HCDR1 that is an HCDR1 in SEQ ID NO: 189, a HCDR2 that is an HCDR2 in SEQ ID NO: 189, a HCDR3 that is an HCDR3 in SEQ ID NO: 189, a LCDR1 that is an LCDR1 in SEQ ID NO: 189, a LCDR2 that is an LCDR2 in SEQ ID NO: 189, and LCDR3 that is an LCDR3 in SEQ ID NO: 189;   (e) a HCDR1 that is an HCDR1 in SEQ ID NO: 190, a HCDR2 that is an HCDR2 in SEQ ID NO: 190, a HCDR3 that is an HCDR3 in SEQ ID NO: 190, a LCDR1 that is an LCDR1 in SEQ ID NO: 190, a LCDR2 that is an LCDR2 in SEQ ID NO: 190, and LCDR3 that is an LCDR3 in SEQ ID NO: 190;   (f) a HCDR1 that is an HCDR1 in SEQ ID NO: 191, a HCDR2 that is an HCDR2 in SEQ ID NO: 191, a HCDR3 that is an HCDR3 in SEQ ID NO: 191, a LCDR1 that is an LCDR1 in SEQ ID NO: 191, a LCDR2 that is an LCDR2 in SEQ ID NO: 191, and LCDR3 that is an LCDR3 in SEQ ID NO: 191;   (g) a VH that is a VH in SEQ ID NO: 186, and a VL that is a VL in SEQ ID NO: 186;   (h) a VH that is a VH in SEQ ID NO: 187, and a VL that is a VL in SEQ ID NO: 187;   (i) a VH that is a VH in SEQ ID NO: 188, and a VL that is a VL in SEQ ID NO: 188;   (j) a VH that is a VH in SEQ ID NO: 189, and a VL that is a VL in SEQ ID NO: 189;   (k) a VH that is a VH in SEQ ID NO: 190, and a VL that is a VL in SEQ ID NO: 190; or   (l) a VH that is a VH in SEQ ID NO: 191, and a VL that is a VL in SEQ ID NO: 191.   
     
     
         45 . The CoStAR of  claim 44 , which further comprises an N-terminal signal peptide. 
     
     
         46 . The CoStAR of  claim 45 , wherein the N-terminal signal peptide comprises the signal peptide of h-oncostatin M (OSM). 
     
     
         47 . The CoStAR of  claim 44 , wherein the CoStAR comprises the amino acid sequence of SEQ ID NO: 19. 
     
     
         48 . The CoStAR of  claim 44 , wherein the CoStAR further comprises a linker, wherein the linker comprises the amino acid sequence of SEQ ID NO: 18. 
     
     
         49 . The CoStAR of  claim 44 , wherein the extracellular binding domain comprises a HCDR1 that is an HCDR1 in SEQ ID NO: 186, a HCDR2 that is an HCDR2 in SEQ ID NO: 186, a HCDR3 that is an HCDR3 in SEQ ID NO: 186, a LCDR1 that is an LCDR1 in SEQ ID NO: 186, a LCDR2 that is an LCDR2 in SEQ ID NO: 186, and LCDR3 that is an LCDR3 in SEQ ID NO: 186. 
     
     
         50 . The CoStAR of  claim 44 , wherein the extracellular binding domain comprises a HCDR1 that is an HCDR1 in SEQ ID NO: 187, a HCDR2 that is an HCDR2 in SEQ ID NO: 187, a HCDR3 that is an HCDR3 in SEQ ID NO: 187, a LCDR1 that is an LCDR1 in SEQ ID NO: 187, a LCDR2 that is an LCDR2 in SEQ ID NO: 187, and LCDR3 that is an LCDR3 in SEQ ID NO: 187. 
     
     
         51 . The CoStAR of  claim 44 , wherein the extracellular binding domain comprises a HCDR1 that is an HCDR1 in SEQ ID NO: 188, a HCDR2 that is an HCDR2 in SEQ ID NO: 188, a HCDR3 that is an HCDR3 in SEQ ID NO: 188, a LCDR1 that is an LCDR1 in SEQ ID NO: 188, a LCDR2 that is an LCDR2 in SEQ ID NO: 188, and LCDR3 that is an LCDR3 in SEQ ID NO: 188. 
     
     
         52 . The CoStAR of  claim 44 , wherein the extracellular binding domain comprises a HCDR1 that is an HCDR1 in SEQ ID NO: 189, a HCDR2 that is an HCDR2 in SEQ ID NO: 189, a HCDR3 that is an HCDR3 in SEQ ID NO: 189, a LCDR1 that is an LCDR1 in SEQ ID NO: 189, a LCDR2 that is an LCDR2 in SEQ ID NO: 189, and LCDR3 that is an LCDR3 in SEQ ID NO: 189. 
     
     
         53 . The CoStAR of  claim 44 , wherein the extracellular binding domain comprises a HCDR1 that is an HCDR1 in SEQ ID NO: 190, a HCDR2 that is an HCDR2 in SEQ ID NO: 190, a HCDR3 that is an HCDR3 in SEQ ID NO: 190, a LCDR1 that is an LCDR1 in SEQ ID NO: 190, a LCDR2 that is an LCDR2 in SEQ ID NO: 190, and LCDR3 that is an LCDR3 in SEQ ID NO: 190. 
     
     
         54 . The CoStAR of  claim 44 , wherein the extracellular binding domain comprises a HCDR1 that is an HCDR1 in SEQ ID NO: 191, a HCDR2 that is an HCDR2 in SEQ ID NO: 191, a HCDR3 that is an HCDR3 in SEQ ID NO: 191, a LCDR1 that is an LCDR1 in SEQ ID NO: 191, a LCDR2 that is an LCDR2 in SEQ ID NO: 191, and LCDR3 that is an LCDR3 in SEQ ID NO: 191. 
     
     
         55 . The CoStAR of  claim 44 , wherein the extracellular binding domain comprises a VH that is a VH in SEQ ID NO: 186, and a VL that is a VL in SEQ ID NO: 186. 
     
     
         56 . The CoStAR of  claim 44 , wherein the extracellular binding domain comprises a VH that is a VH in SEQ ID NO: 187, and a VL that is a VL in SEQ ID NO: 187. 
     
     
         57 . The CoStAR of  claim 44 , wherein the extracellular binding domain comprises a VH that is a VH in SEQ ID NO: 188, and a VL that is a VL in SEQ ID NO: 188. 
     
     
         58 . The CoStAR of  claim 44 , wherein the extracellular binding domain comprises a VH that is a VH in SEQ ID NO: 189, and a VL that is a VL in SEQ ID NO: 189. 
     
     
         59 . The CoStAR of  claim 44 , wherein the extracellular binding domain comprises a VH that is a VH in SEQ ID NO: 190, and a VL that is a VL in SEQ ID NO: 190. 
     
     
         60 . The CoStAR of  claim 44 , wherein the extracellular binding domain comprises a VH that is a VH in SEQ ID NO: 191, and a VL that is a VL in SEQ ID NO: 191. 
     
     
         61 . The CoStAR of  claim 44 , wherein the CoStAR comprises the amino acid sequence of SEQ ID NO: 192, lacking the signal peptide of SEQ ID NO: 1. 
     
     
         62 . The CoStAR of  claim 44 , wherein the CoStAR comprises the amino acid sequence of SEQ ID NO: 210, lacking the signal peptide of SEQ ID NO: 1. 
     
     
         63 . The CoStAR of  claim 44 , wherein the CoStAR comprises the amino acid sequence of SEQ ID NO: 228, lacking the signal peptide of SEQ ID NO: 1. 
     
     
         64 . The CoStAR of  claim 44 , wherein the CoStAR comprises the amino acid sequence of SEQ ID NO: 246, lacking the signal peptide of SEQ ID NO: 1. 
     
     
         65 . The CoStAR of  claim 44 , wherein the CoStAR comprises the amino acid sequence of SEQ ID NO: 264, lacking the signal peptide of SEQ ID NO: 1. 
     
     
         66 . The CoStAR of  claim 44 , wherein the CoStAR comprises the amino acid sequence of SEQ ID NO: 282, lacking the signal peptide of SEQ ID NO: 1. 
     
     
         67 . The CoStAR of  claim 44 , wherein the extracellular binding domain is connected to a linker having an amino acid sequence of SEQ ID NO: 18, which is connected to a an amino acid sequence of SEQ ID NO: 19 that comprises a spacer sequence and a transmembrane sequence, that is in turn connected to the CD28 signaling domain, that is in turn connected to the CD40 signaling domain. 
     
     
         68 . A cell which expresses a CoStAR, the CoStAR comprising:
 an extracellular binding domain that binds to mesothelin (MSLN);   a CD28 signaling domain, wherein the CD28 signaling domain comprises the amino acid sequence of SEQ ID NO: 25; and   a CD40 signaling domain, wherein the CD40 signaling domain comprises the amino acid sequence of SEQ ID NO: 32,   wherein the extracellular binding domain comprises any one of:   (a) a HCDR1 that is an HCDR1 in SEQ ID NO: 186, a HCDR2 that is an HCDR2 in SEQ ID NO: 186, a HCDR3 that is an HCDR3 in SEQ ID NO: 186, a LCDR1 that is an LCDR1 in SEQ ID NO: 186, a LCDR2 that is an LCDR2 in SEQ ID NO: 186, and LCDR3 that is an LCDR3 in SEQ ID NO: 186;   (b) a HCDR1 that is an HCDR1 in SEQ ID NO: 187, a HCDR2 that is an HCDR2 in SEQ ID NO: 187, a HCDR3 that is an HCDR3 in SEQ ID NO: 187, a LCDR1 that is an LCDR1 in SEQ ID NO: 187, a LCDR2 that is an LCDR2 in SEQ ID NO: 187, and LCDR3 that is an LCDR3 in SEQ ID NO: 187;   (c) a HCDR1 that is an HCDR1 in SEQ ID NO: 188, a HCDR2 that is an HCDR2 in SEQ ID NO: 188, a HCDR3 that is an HCDR3 in SEQ ID NO: 188, a LCDR1 that is an LCDR1 in SEQ ID NO: 188, a LCDR2 that is an LCDR2 in SEQ ID NO: 188, and LCDR3 that is an LCDR3 in SEQ ID NO: 188;   (d) a HCDR1 that is an HCDR1 in SEQ ID NO: 189, a HCDR2 that is an HCDR2 in SEQ ID NO: 189, a HCDR3 that is an HCDR3 in SEQ ID NO: 189, a LCDR1 that is an LCDR1 in SEQ ID NO: 189, a LCDR2 that is an LCDR2 in SEQ ID NO: 189, and LCDR3 that is an LCDR3 in SEQ ID NO: 189;   (e) a HCDR1 that is an HCDR1 in SEQ ID NO: 190, a HCDR2 that is an HCDR2 in SEQ ID NO: 190, a HCDR3 that is an HCDR3 in SEQ ID NO: 190, a LCDR1 that is an LCDR1 in SEQ ID NO: 190, a LCDR2 that is an LCDR2 in SEQ ID NO: 190, and LCDR3 that is an LCDR3 in SEQ ID NO: 190;   (f) a HCDR1 that is an HCDR1 in SEQ ID NO: 191, a HCDR2 that is an HCDR2 in SEQ ID NO: 191, a HCDR3 that is an HCDR3 in SEQ ID NO: 191, a LCDR1 that is an LCDR1 in SEQ ID NO: 191, a LCDR2 that is an LCDR2 in SEQ ID NO: 191, and LCDR3 that is an LCDR3 in SEQ ID NO: 191;   (g) a VH that is a VH in SEQ ID NO: 186, and a VL that is a VL in SEQ ID NO: 186;   (h) a VH that is a VH in SEQ ID NO: 187, and a VL that is a VL in SEQ ID NO: 187;   (i) a VH that is a VH in SEQ ID NO: 188, and a VL that is a VL in SEQ ID NO: 188;   (j) a VH that is a VH in SEQ ID NO: 189, and a VL that is a VL in SEQ ID NO: 189;   (k) a VH that is a VH in SEQ ID NO: 190, and a VL that is a VL in SEQ ID NO: 190; or   (l) a VH that is a VH in SEQ ID NO: 191, and a VL that is a VL in SEQ ID NO: 191.   
     
     
         69 . The cell of  claim 68 , wherein the cell comprises an alpha-beta T cell, gamma-delta T cell, T regulatory cell, TIL, NKT cell or NK cell. 
     
     
         70 . The cell of  claim 68 , wherein the cell coexpresses a CAR or a TCR. 
     
     
         71 . A fusion protein, wherein the fusion protein comprises:
 i. a first sequence, wherein the first sequence comprises one or more of:
 a. a HCDR1 that is an HCDR1 in SEQ ID NO: 186, a HCDR2 that is an HCDR2 in SEQ ID NO: 186, a HCDR3 that is an HCDR3 in SEQ ID NO: 186, a LCDR1 that is an LCDR1 in SEQ ID NO: 186, a LCDR2 that is an LCDR2 in SEQ ID NO: 186, and LCDR3 that is an LCDR3 in SEQ ID NO: 186; 
 b. a HCDR1 that is an HCDR1 in SEQ ID NO: 187, a HCDR2 that is an HCDR2 in SEQ ID NO: 187, a HCDR3 that is an HCDR3 in SEQ ID NO: 187, a LCDR1 that is an LCDR1 in SEQ ID NO: 187, a LCDR2 that is an LCDR2 in SEQ ID NO: 187, and LCDR3 that is an LCDR3 in SEQ ID NO: 187; 
 c. a HCDR1 that is an HCDR1 in SEQ ID NO: 188, a HCDR2 that is an HCDR2 in SEQ ID NO: 188, a HCDR3 that is an HCDR3 in SEQ ID NO: 188, a LCDR1 that is an LCDR1 in SEQ ID NO: 188, a LCDR2 that is an LCDR2 in SEQ ID NO: 188, and LCDR3 that is an LCDR3 in SEQ ID NO: 188; 
 d. a HCDR1 that is an HCDR1 in SEQ ID NO: 189, a HCDR2 that is an HCDR2 in SEQ ID NO: 189, a HCDR3 that is an HCDR3 in SEQ ID NO: 189, a LCDR1 that is an LCDR1 in SEQ ID NO: 189, a LCDR2 that is an LCDR2 in SEQ ID NO: 189, and LCDR3 that is an LCDR3 in SEQ ID NO: 189; 
 e. a HCDR1 that is an HCDR1 in SEQ ID NO: 190, a HCDR2 that is an HCDR2 in SEQ ID NO: 190, a HCDR3 that is an HCDR3 in SEQ ID NO: 190, a LCDR1 that is an LCDR1 in SEQ ID NO: 190, a LCDR2 that is an LCDR2 in SEQ ID NO: 190, and LCDR3 that is an LCDR3 in SEQ ID NO: 190; 
 f. a HCDR1 that is an HCDR1 in SEQ ID NO: 191, a HCDR2 that is an HCDR2 in SEQ ID NO: 191, a HCDR3 that is an HCDR3 in SEQ ID NO: 191, a LCDR1 that is an LCDR1 in SEQ ID NO: 191, a LCDR2 that is an LCDR2 in SEQ ID NO: 191, and LCDR3 that is an LCDR3 in SEQ ID NO: 191; 
 g. a VH that is a VH in SEQ ID NO: 186, and a VL that is a VL in SEQ ID NO: 186; 
 h. a VH that is a VH in SEQ ID NO: 187, and a VL that is a VL in SEQ ID NO: 187; 
 i. a VH that is a VH in SEQ ID NO: 188, and a VL that is a VL in SEQ ID NO: 188; 
 j. a VH that is a VH in SEQ ID NO: 189, and a VL that is a VL in SEQ ID NO: 189; 
 k. a VH that is a VH in SEQ ID NO: 190, and a VL that is a VL in SEQ ID NO: 190; or 
 (a) a VH that is a VH in SEQ ID NO: 191, and a VL that is a VL in SEQ ID NO: 191; 
   ii. a second sequence that is a transmembrane domain;   iii. a third sequence that comprises the amino acid sequence of SEQ ID NO: 25; and   iv. a fourth sequence that comprises the amino acid sequence of SEQ ID NO: 32, wherein the first sequence is linked to the second sequence, wherein the second sequence is linked to the third sequence, and wherein the third sequence is linked to the fourth sequence.   
     
     
         72 . A method of cell therapy comprising:
 a) identifying a subject, wherein the subject has cancer that expresses MSLN; and   b) administering any a CoStAR that comprises:   an extracellular binding domain that binds to mesothelin (MSLN),   a transmembrane domain,   a CD28 signaling domain that comprises the amino acid sequence of SEQ ID NO: 25; and   a CD40 signaling domain, wherein the CD40 signaling domain comprises the amino acid sequence of SEQ ID NO: 32,   wherein the extracellular binding domain is linked to the transmembrane domain, wherein the transmembrane domain is linked to the CD28 signaling domain, wherein the CD28 signaling domain is linked to the CD40 domain, and   wherein the extracellular binding domain comprises any one or more of:   (a) a HCDR1 that is an HCDR1 in SEQ ID NO: 186, a HCDR2 that is an HCDR2 in SEQ ID NO: 186, a HCDR3 that is an HCDR3 in SEQ ID NO: 186, a LCDR1 that is an LCDR1 in SEQ ID NO: 186, a LCDR2 that is an LCDR2 in SEQ ID NO: 186, and LCDR3 that is an LCDR3 in SEQ ID NO: 186;   (b) a HCDR1 that is an HCDR1 in SEQ ID NO: 187, a HCDR2 that is an HCDR2 in SEQ ID NO: 187, a HCDR3 that is an HCDR3 in SEQ ID NO: 187, a LCDR1 that is an LCDR1 in SEQ ID NO: 187, a LCDR2 that is an LCDR2 in SEQ ID NO: 187, and LCDR3 that is an LCDR3 in SEQ ID NO: 187;   (c) a HCDR1 that is an HCDR1 in SEQ ID NO: 188, a HCDR2 that is an HCDR2 in SEQ ID NO: 188, a HCDR3 that is an HCDR3 in SEQ ID NO: 188, a LCDR1 that is an LCDR1 in SEQ ID NO: 188, a LCDR2 that is an LCDR2 in SEQ ID NO: 188, and LCDR3 that is an LCDR3 in SEQ ID NO: 188;   (d) a HCDR1 that is an HCDR1 in SEQ ID NO: 189, a HCDR2 that is an HCDR2 in SEQ ID NO: 189, a HCDR3 that is an HCDR3 in SEQ ID NO: 189, a LCDR1 that is an LCDR1 in SEQ ID NO: 189, a LCDR2 that is an LCDR2 in SEQ ID NO: 189, and LCDR3 that is an LCDR3 in SEQ ID NO: 189;   (e) a HCDR1 that is an HCDR1 in SEQ ID NO: 190, a HCDR2 that is an HCDR2 in SEQ ID NO: 190, a HCDR3 that is an HCDR3 in SEQ ID NO: 190, a LCDR1 that is an LCDR1 in SEQ ID NO: 190, a LCDR2 that is an LCDR2 in SEQ ID NO: 190, and LCDR3 that is an LCDR3 in SEQ ID NO: 190;   (f) a HCDR1 that is an HCDR1 in SEQ ID NO: 191, a HCDR2 that is an HCDR2 in SEQ ID NO: 191, a HCDR3 that is an HCDR3 in SEQ ID NO: 191, a LCDR1 that is an LCDR1 in SEQ ID NO: 191, a LCDR2 that is an LCDR2 in SEQ ID NO: 191, and LCDR3 that is an LCDR3 in SEQ ID NO: 191;   (g) a VH that is a VH in SEQ ID NO: 186, and a VL that is a VL in SEQ ID NO: 186;   (h) a VH that is a VH in SEQ ID NO: 187, and a VL that is a VL in SEQ ID NO: 187;   (i) a VH that is a VH in SEQ ID NO: 188, and a VL that is a VL in SEQ ID NO: 188;   (j) a VH that is a VH in SEQ ID NO: 189, and a VL that is a VL in SEQ ID NO: 189;   (k) a VH that is a VH in SEQ ID NO: 190, and a VL that is a VL in SEQ ID NO: 190; or   (1) a VH that is a VH in SEQ ID NO: 191, and a VL that is a VL in SEQ ID NO: 191.

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