Nucleic acid encoding a humanized anti-BCMA chimeric antigen receptor

Patent metadata

Field	Value
Publication number	US-10174095-B2
Application number	US-201514805193-A
Country	US
Kind code	B2
Filing date	Jul 21, 2015
Priority date	Jul 21, 2014
Publication date	Jan 8, 2019
Grant date	Jan 8, 2019

Abstract

The invention provides compositions and methods for treating diseases associated with expression of BCMA. The invention also relates to chimeric antigen receptor (CAR) specific to BCMA vectors encoding the same, and recombinant T cells comprising the BCMA CAR. The invention also includes methods of administering a genetically modified T cell expressing a CAR that comprises a BCMA binding domain.

First claim

What is claimed is:

1. An isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an anti-B-cell maturation antigen (BCMA) binding domain, a transmembrane domain, and an intracellular signaling domain, wherein said anti-BCMA binding domain comprises:
(i) a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 394, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 434, a heavy chain complementary determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 474, a light chain complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 514, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 554, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 594;
(ii) a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 634, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 674, a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 714, a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 754, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 794, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 834; or
(iii) a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 874, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 914, a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 954, a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 994, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 1034, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 1074, and wherein:
the intracellular signaling domain comprises a primary signaling domain comprising a functional signaling domain of CD3 zeta or an amino acid sequence with 95-99% identity thereof.

2. The isolated nucleic acid molecule of claim 1 , which encodes a CAR comprising:
(i) the amino acid sequence of a light chain variable region comprising the amino acid sequence of SEQ ID NO: 94;
(ii) an amino acid sequence having at least one, two or three modifications but not more than 30, 20 or 10 modifications of the amino acid sequence of a light chain variable region comprising the amino acid sequence of SEQ ID NO: 94; or
(iii) an amino acid sequence with 95-99% identity to the amino acid sequence of a light chain variable region comprising the amino acid sequence of SEQ ID NO: 94.

3. The isolated nucleic acid molecule of claim 1 , which encodes a CAR comprising:
(i) the amino acid sequence of a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 79;
(ii) an amino acid sequence having at least one, two or three modifications but not more than 30, 20 or 10 modifications of the amino acid sequence of a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 79; or
(iii) an amino acid sequence with 95-99% identity to the amino acid sequence of a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 79.

4. The isolated nucleic acid molecule of claim 1 , which encodes a CAR comprising the amino acid sequence of a light chain variable region comprising the amino acid sequence of SEQ ID NO: 94, and the amino acid sequence of a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 79.

5. The isolated nucleic acid molecule of claim 1 , comprising a nucleic acid sequence encoding the anti-BCMA binding domain, wherein the nucleic acid sequence comprises the nucleotide sequence of SEQ ID NO: 64, or a sequence with 95-99% identity thereof.

6. The isolated nucleic acid molecule of claim 1 , wherein:
(i) the encoded CAR comprises a transmembrane domain that comprises a transmembrane domain of a protein selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154;
(ii) the encoded transmembrane domain comprises the amino acid sequence of SEQ ID NO: 6, an amino acid sequence comprising at least one, two or three modifications but not more than 20, 10 or 5 modifications of the amino acid sequence of SEQ ID NO:6, or a sequence with 95-99% identity to the amino acid sequence of SEQ ID NO:6; or
(iii) the isolated nucleic acid molecule comprises a nucleic acid sequence encoding the transmembrane domain, wherein the nucleic acid sequence comprises the nucleotide sequence of SEQ ID NO:17, or a nucleotide sequence with 95-99% identity thereof.

7. The isolated nucleic acid molecule of claim 1 , wherein the encoded anti-BCMA binding domain comprises:
(i) the amino acid sequence of SEQ ID NO: 49;
(ii) an amino acid sequence having at least one, two or three modifications but not more than 30, 20 or 10 modifications to SEQ ID NO: 49; or
(iii) an amino acid sequence with 95-99% identity to SEQ ID NO: 49.

8. The isolated nucleic acid molecule of claim 1 , wherein the encoded anti-BCMA binding domain is connected to the transmembrane domain by a hinge region, wherein (i) the encoded hinge region comprises the amino acid sequence of SEQ ID NO:2, or a sequence with 95-99% identity thereof; or (ii) the isolated nucleic acid molecule comprises a nucleic acid sequence encoding the hinge region, wherein the nucleic acid sequence comprises the nucleotide sequence of SEQ ID NO: 13, or a sequence with 95-99% identity thereof.

9. The isolated nucleic acid molecule of claim 1 , wherein the encoded intracellular signaling domain comprises a costimulatory domain, wherein the costimulatory domain comprises a functional signaling domain derived from a protein selected from the group consisting of MHC class I molecules, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, 4-1BB (CD137), B7-H3, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, and a ligand that specifically binds with CD83.

10. The isolated nucleic acid molecule of claim 1 , wherein the encoded intracellular signaling domain comprises a costimulatory domain, wherein the costimulatory domain comprises the amino acid sequence of SEQ ID NO:7, or a sequence with 95-99% identity to the amino acid sequence of SEQ ID NO:7.

11. The isolated nucleic acid molecule of claim 1 , wherein the encoded intracellular signaling domain comprises a costimulatory domain, wherein the isolated nucleic acid molecule comprises a nucleic acid sequence encoding the costimulatory domain, wherein the nucleic acid sequence comprises the nucleotide sequence of SEQ ID NO:18, or a sequence with 95-99% identity thereof.

12. The isolated nucleic acid molecule of claim 1 , wherein the encoded intracellular signaling domain comprises a functional signaling domain of 4-1BB and a functional signaling domain of CD3 zeta.

13. The isolated nucl

Assignees

• Novartis Ag
• Univ Pennsylvania

Inventors

• Brogdon Jennifer
• Choi Eugene
• Ebersbach Hilmar Erhard
• Glass David
• Huet Heather
• June Carl H
• Mannick Joan
• Milone Michael C
• Murphy Leon
• Plesa Gabriela
• Richardson Celeste
• Ruella Marco
• Singh Reshma
• Wang Yongqiang
• Wu Qilong

Classifications

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title