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1. WO2020191485 - ANTI-EGFRVIII ANTIBODIES AND ANTIGEN-BINDING FRAGMENTS THEREOF

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[ EN ]
CLAIMS:

1. An antigen-binding agent comprising an antigen-binding domain of an antibody that specifically binds to epidermal growth factor receptor variant III (EGFRvlll), wherein the antigen-binding domain comprises:

a. light chain variable region comprising a CDRL1 having the amino acid sequence of SEQ ID NO:8, a CDRL2 sequence of SEQ ID NO:9 and a CDRL3 sequence of SEQ ID NO:10 and a heavy chain variable region comprising a CDRH1 sequence of SEQ ID NO:13, a CDRH2 sequence of SEQ ID NO:14 and a CDRH3 sequence of SEQ ID NO:15;

b. a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO:18, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:19 and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:20 and a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:23, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:24 and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:25;

c. a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO:28, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:29 and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:30 and a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:33, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:34 and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:35;

d. a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO:38, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:39 and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:40 and a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:43, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:44 and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:45;

e. a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO:48, a CDRL2 having the amino acid sequence set forth in

SEQ ID NO:49 and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:50 and a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:53, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:54 and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:55;

f. a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO:58, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:59 and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:60 and a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:63, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:64 and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:65;

g. a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO:68, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:69 and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:70 and a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:78, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:79 and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:80, and;

h. a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO:73, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:74 and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:75 and a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:78, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:79 and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:80.

2. The antigen-binding agent of claim 1 , wherein the antigen binding agent comprises; a. A light chain variable region comprising a sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:7 or substantially identical to SEQ ID NO:7 and a heavy chain variable region comprising a sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:12 or substantially identical to SEQ ID NO:12;

b. A light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 17 or substantially identical to SEQ ID NO:17 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:22 or substantially identical to SEQ ID NO:22;

c. A light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:27 or substantially identical to SEQ ID NO:27 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:32 or substantially identical to SEQ ID NO:32;

d. A light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 37 or substantially identical to SEQ ID NO:37 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:42 or substantially identical to SEQ ID NO:42;

e. A light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:47 or substantially identical to SEQ ID NO:47 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:52 or substantially identical to SEQ ID NO:52;

f. A light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:57 or substantially identical to SEQ ID NO:57 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:62 or substantially identical to SEQ ID NO:62;

g. A light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:67 or substantially identical to SEQ ID NO:67 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:77 or substantially identical to SEQ ID NO:77, the amino acid set forth in SEQ ID NO:92 or substantially identical to SEQ ID NO:92 or the amino acid sequence set forth in SEQ ID NO:102 or substantially identical to SEQ ID NO:102, or;

h. A light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:72 or substantially identical to SEQ ID NO: 72 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:77 or substantially identical to SEQ ID NO:77 or the amino acid set forth in SEQ ID NO:92 or substantially identical to SEQ ID NO:92.

3. The antigen-binding agent of claim 1 or 2, wherein the antigen-binding agent is an antibody or antigen-binding fragment thereof, a chimeric antigen receptor, a bi-specific T-cell engager, a bispecific killer cell engager, a trispecific killer cell engager or any immunotherapeutic compound.

4. An antibody or an antigen-binding fragment thereof which specifically binds to EGFRvlll and comprising:

a. light chain variable region comprising a CDRL1 having the amino acid sequence of SEQ ID NO:8, a CDRL2 sequence of SEQ ID NO:9 and a CDRL3 sequence of SEQ ID NO:10 and a heavy chain variable region comprising a CDRH1 sequence of SEQ ID NO:13, a CDRH2 sequence of SEQ ID NO:14 and a CDRH3 sequence of SEQ ID NO:15;

b. a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO:18, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:19 and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:20 and a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:23, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:24 and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:25;

c. a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO:28, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:29 and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:30 and a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:33, a CDRH2 having the amino acid

sequence set forth in SEQ ID NO:34 and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:35;

d. a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO:38, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:39 and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:40 and a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:43, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:44 and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:45;

e. a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO:48, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:49 and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:50 and a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:53, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:54 and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:55;

f. a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO:58, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:59 and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:60 and a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:63, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:64 and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:65;

g. a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO:68, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:69 and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:70 and a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:78, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:79 and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:80, and;

h. a light chain variable region comprising a CDRL1 having the amino acid sequence set forth in SEQ ID NO:73, a CDRL2 having the amino acid sequence set forth in SEQ ID NO:74 and a CDRL3 having the amino acid sequence set forth in SEQ ID NO:75 and a heavy chain variable region comprising a CDRH1 having the amino acid sequence set forth in SEQ ID NO:78, a CDRH2 having the amino acid sequence set forth in SEQ ID NO:79 and a CDRH3 having the amino acid sequence set forth in SEQ ID NO:80.

5. The antibody or antigen-binding fragment thereof of claim 4, wherein the antibody is monoclonal antibody, a polyclonal antibody, a humanized antibody, a chimeric antibody, a human antibody, a single chain antibody, or a multispecific antibody.

6. An antibody or an antigen-binding fragment thereof which specifically binds to EGFRvlll comprising:

a. a light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 118 or substantially identical to SEQ ID NO:1 18 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:116 or substantially identical to SEQ ID NO:1 16;

b. A light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 115 or substantially identical to SEQ ID NO:1 15 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:116 or substantially identical to SEQ ID NO:1 16, or;

c. A light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 118 or substantially identical to SEQ ID NO:1 18 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:62 or substantially identical to SEQ ID NO:62.

7. An antibody or an antigen-binding fragment thereof which specifically binds to EGFRvlll and comprising:

a. A light chain variable region comprising a sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:7 or substantially identical to SEQ ID NO:7 and a heavy chain variable region comprising a sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:12 or substantially identical to SEQ ID NO:12;

b. A light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 17 or substantially identical to SEQ ID NO:17 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:22 or substantially identical to SEQ ID NO:22;

c. A light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:27 or substantially identical to SEQ ID NO:27 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:32 or substantially identical to SEQ ID NO:32;

d. A light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 37 or substantially identical to SEQ ID NO:37 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:42 or substantially identical to SEQ ID NO:42;

e. A light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:47 or substantially identical to SEQ ID NO:47 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:52 or substantially identical to SEQ ID NO:52;

f. A light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:57 or substantially identical to SEQ ID NO:57 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:62 or substantially identical to SEQ ID NO:62;

g. A light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:67 or substantially identical to SEQ ID NO:67 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:77 or substantially identical to SEQ ID NO:77, the amino acid set forth in SEQ ID NO:92 or substantially identical to SEQ ID NO:92 or the amino acid sequence set forth in SEQ ID NO:102 or substantially identical to SEQ ID NO:102, or;

h. A light chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:72 or substantially identical to SEQ ID NO: 72 and a heavy chain variable region comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:77 or substantially identical to SEQ ID NO:77 or the amino acid set forth in SEQ ID NO:92 or substantially identical to SEQ ID NO:92.

8. The antibody or antigen-binding fragment thereof of any one of claim 4 to 7, wherein the antibody or antigen-binding fragment thereof comprises a human lgG1 constant region.

9. The antibody or antigen-binding fragment thereof of any one of claims 4 to 8, wherein the antibody or antigen-binding fragment thereof comprises a human lgG2 constant region.

10. An antibody or an antigen-binding fragment thereof which specifically binds to EGFRvlll and comprising a sequence selected from the group consisting of:

a. A light chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:108 or substantially identical to SEQ ID NO:108 and a heavy chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:107 or substantially identical to SEQ ID NO:107, and;

b. A light chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:1 10 or substantially identical to SEQ ID NO:1 10 and a heavy chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO:109 or substantially identical to SEQ ID NO:109.

1 1 . The antibody or antigen-binding fragment thereof of any one of claims 4 to 10, wherein the antigen-binding fragment comprises a scFv, a Fab, a Fab' or a (Fab')2.

12. The antibody or antigen-binding fragment thereof of any one of claims 4 to 1 1 , wherein the antibody or antigen-binding fragment thereof is linked to a cargo molecule.

13. The antibody or antigen-binding fragment thereof of claim 12, wherein the cargo molecule comprises a therapeutic moiety.

14. The antibody or antigen-binding fragment of claim 13, wherein the therapeutic moiety comprises a cytotoxic agent, a cytostatic agent, an anti-cancer agent or a radiotherapeutic.

15. The antibody or antigen-binding fragment thereof of claim 13, wherein the antibody or antigen-binding fragment thereof is conjugated with a detectable moiety.

16. A pharmaceutical composition comprising the antigen-binding agent or the antibody or antigen-binding fragment of any one of claims 1 to 15 and a pharmaceutically acceptable carrier, diluent or excipient.

17. A nucleic acid molecule encoding a light chain variable region and/or a heavy chain variable region of the antigen-binding agent or antibody or antigen-binding fragment thereof of any one of claims 1 to 1 1 .

18. The nucleic acid molecule of claim 17, wherein the nucleic acid is selected from the group consisting of:

a. a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO: 1 1 and/or a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:16;

b. a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:21 and/or a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:26;

c. a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:31 and/or a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:36;

d. a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:41 and/or a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:46;

e. a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:51 and/or a nucleic acid molecule

comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:56;

f. a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:61 and/or a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:66;

g. a nucleic acid molecule comprising the nucleotide sequence a sequence at least 80% identical to set forth in SEQ ID NO:71 and/or a nucleic acid comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:81 ;

h. a nucleic acid comprising the nucleotide sequence a sequence at least 80% identical to set forth in SEQ ID NO:76 and/or a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:81 ;

i. a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:86 and/or a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:96;

j. a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:91 and/or a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:96, or;

k. a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:101 and/or a nucleic acid molecule comprising a sequence at least 80% identical to the nucleotide sequence set forth in SEQ ID NO:106.

19. A kit comprising at least one of the antigen-binding agent or antibody or antigen-binding fragment thereof of any one of claims 1 to 15.

20. A vector or set of vectors comprising a nucleic acid sequence encoding a light chain variable region and a heavy chain variable region of the antigen-binding agent or antibody or antigen-binding fragment thereof of any one of claims 1 to 11.

21. An isolated cell comprising the vector or set of vectors of claim 20.

22. The isolated cells of claim 21 , wherein said cell is capable of expressing, assembling and/or secreting an antibody or antigen-binding fragment thereof.

23. A kit comprising a first vial comprising a nucleotide or vector encoding the light chain of the antigen-binding agent or antibody or antigen-binding fragment thereof of any one of claims 1 to 1 1 and a second vial comprising a nucleotide or vector encoding the heavy chain of the antibody or antigen-binding fragment thereof of any one of claims 1 to 11.

24. A method of treating cancer comprising cells expressing EGFRvlll, the method comprising administering the antibody or antigen-binding fragment thereof of any one of claims 4 to 15 to a subject in need.

25. The method of claim 24, wherein the antibody is used in combination with a chemotherapeutic.

26. The method of any one of claims 24 or 25, wherein the subject in need has or is suspected of having gliobastoma multiforme.

27. The method of any one of claims 24 or 25, wherein the subject in need has or is suspected of having a carcinoma.

28. The method of claim 27, wherein the carcinoma comprises breast carcinoma or HNSCC.

29. A method of detecting EGFRvlll, the method comprising contacting a sample comprising or suspected of comprising EGFRvlll with the antibody or antigen-binding fragment of any one of claims 1 to 15.

30. A method of making the antibody or antigen-binding fragment thereof of any one of claims 4 to 11 , comprising culturing a cell comprising nucleic acids encoding said antibody or antigen-binding fragment so that the antibody or antigen-binding fragment thereof is produced.

31. The method of claim 30, further comprising conjugating the antibody or antigen-binding fragment thereof with a cargo molecule.

32. The method of claim 31 , wherein the cargo molecule comprises a therapeutic moiety.

33. The method of claim 31 , wherein the cargo molecule comprises a detectable moiety.

34. A method of treating subject having a cancer associated with EGFRvlll expression, the method comprising administering cells expressing the antigen-binding agent of any one of claims 1 to 3, wherein the antigen-binding agent is a chimeric antigen receptor, a bi specific T-cell engager, a bispecific killer cell engager or a trispecific killer cell engager. 35. The method of claim 34, wherein the subject in need has or is suspected of having glioma.

36. The method of claim 35, wherein the glioma is gliobastoma multiforme.

37. The method of claim 34, wherein the subject in need has or is suspected of having a carcinoma.

38. The method of claim 37, wherein the carcinoma comprises breast carcinoma, oral carcinoma or HNSCC.

39. The method of any one of claims 34 to 38, wherein the cells are T-cells.

40. The method of any one of claims 34 to 38, wherein the cells are NK cells.

41. The method of any one of claims 34 to 40, wherein the cells are immune cells autologous to the subject,

42. An isolated cell population engineered to express the antigen-binding agent of any one of claims 1 to 3.

43. The isolated cell population of claim 42, wherein the isolated cell population is of human origin.

44. The isolated cell population of claim 42 or 43, wherein the isolated cell population comprises T cells, Natural Killer (NK) cells, cytotoxic T cells, regulatory T cells, and combinations thereof.

45. The isolated cell population of claim 44, wherein the isolated cell population comprises T cells.

46. The isolated cell population of claim 45, wherein the T-cells comprise CD4+ T-cells, CD8+ T-cells or a combination thereof.

47. The isolated cell population of claim 44, wherein the isolated cell population comprises NK cells.

48. The isolated cell population of any one of claims 42 to 47, wherein the isolated cell population is engineered to express another chimeric antigen receptor having affinity for another antigen of the same target or of a different target.

49. The isolated cell population of any one of claims 42 to 47, wherein the isolated cell population comprises an host’s immune cells.

50. A pharmaceutical composition comprising the isolated cell population of any one of

claims 42 to 49 and a pharmaceutically acceptable buffer or excipient.