Dosing regimen for GP100-specific TCR—anti-CD3 SCFV fusion protein

1. A method of treating gp100 positive cancer in a patient, comprising:

administering to said patient a plurality of doses of a T cell redirecting bispecific therapeutic which comprises (1) a targeting moiety that binds the YLEPGPVTA (SEQ ID NO:1)-HLA-A2 complex fused to (2) a CD3 binding T cell redirection moiety, wherein the bispecific therapeutic includes

(a) a TCR alpha chain amino acid sequence selected from the group consisting of:

(i) the TCR alpha chain sequence of SEQ ID No: 2, wherein amino acids 1 to 109 are replaced by the sequence of SEQ ID No: 4, wherein amino acid at position 1 is S;

(ii) the TCR alpha chain sequence of SEQ ID No: 2, wherein amino acids 1 to 109 are replaced by the sequence of SEQ ID No: 4, wherein amino acid at position 1 is A;

(iii) the TCR alpha chain sequence of SEQ ID No: 2, wherein amino acids 1 to 109 are replaced by the sequence of SEQ ID No: 4, wherein amino acid at position 1 is G;

(iv) the TCR alpha chain sequence of SEQ ID No: 2, wherein amino acids 1 to 109 are replaced by the sequence of SEQ ID No: 4, wherein amino acid at position 1 is S, and the C-terminus of the alpha chain is truncated by 8 amino acids from F196 to S203 inclusive, based on the numbering of SEQ ID No: 2;

(v) the TCR alpha chain sequence of SEQ ID No: 2, wherein amino acids 1 to 109 are replaced by the sequence of SEQ ID No: 4, wherein amino acid at position 1 is A, and the C-terminus of the alpha chain is truncated by 8 amino acids from F196 to S203 inclusive, based on the numbering of SEQ ID No: 2; and

(vi) the TCR alpha chain sequence of SEQ ID No: 2, wherein amino acids 1 to 109 are replaced by the sequence of SEQ ID No: 4, wherein amino acid at position 1 is G, and the C-terminus of the alpha chain is truncated by 8 amino acids from F196 to S203 inclusive, based on the numbering of SEQ ID No: 2; and

(b) a TCR beta chain-anti-CD3 amino acid sequence selected from the group consisting of:

(vii) the TCR beta chain-anti-CD3 sequence of SEQ ID No: 5, wherein amino acids at positions 1 and 2 are D and I respectively;

(viii) the TCR beta chain-anti-CD3 sequence of SEQ ID No: 5, wherein amino acids at positions 1 and 2 are A and I respectively;

(ix) the TCR beta chain-anti-CD3 sequence of SEQ ID No: 5, wherein amino acids at positions 1 and 2 are A and Q respectively;

(x) the TCR beta chain-anti-CD3 sequence of SEQ ID No: 5, wherein amino acids at positions 1 and 2 are D and I respectively amino acids at positions 108-131 are replaced by RTSGPGDGGKGGPGKGPGGEGTKGTGPGG (SEQ ID No: 6), and amino acids at positions 254-258 are replaced by GGEGGGSEGGGS (SEQ ID No: 7);

(xi) the TCR beta chain-anti-CD3 sequence of SEQ ID No: 5, wherein amino acids at positions 1 and 2 are D and I respectively and amino acid at position 257 is a S and amino acid at position 258 is a G;

(xii) the TCR beta chain-anti-CD3 sequence of SEQ ID No: 5, wherein amino acids at positions 1 and 2 are D and I respectively and amino acid at position 256 is a S and amino acid at position 258 is a G;

(xiii) the TCR beta chain-anti-CD3 sequence of SEQ ID No: 5, wherein amino acids at positions 1 and 2 are D and I respectively and amino acid at position 255 is a S and amino acid at position 258 is a G;

(xiv) the TCR beta chain-anti-CD3 sequence of SEQ ID No: 5, wherein amino acids at positions 1 and 2 are A and Q, and wherein amino acid at position 257 is a S and amino acid at position 258 is a G;

(xv) the TCR beta chain-anti-CD3 sequence of SEQ ID No: 5, wherein amino acids at positions 1 and 2 are A and Q, and wherein amino acid at position 256 is a S and amino acid at position 258 is a G;

(xvi) the TCR beta chain-anti-CD3 sequence of SEQ ID No: 5, wherein amino acids at positions 1 and 2 are A and Q, and wherein amino acid at position 255 is a S and amino acid at position 258 is a G;

(xvii) the TCR beta chain-anti-CD3 sequence of SEQ ID No: 5, wherein amino acid at positions 1 and 2 are A and I respectively, and wherein amino acid at position 257 is a S and amino acid at position 258 is a G;

(xviii) the TCR beta chain-anti-CD3 sequence of SEQ ID No: 5, wherein amino acid at positions 1 and 2 are A and I respectively, and wherein amino acid at position 256 is a S and amino acid at position 258 is a G; and

(xix) the TCR beta chain-anti-CD3 sequence of SEQ ID No: 5, wherein amino acid at positions 1 and 2 are A and I respectively, and wherein amino acid at position 255 is a S and amino acid at position 258 is a G; and

wherein

the method comprises administration of:

(a) at least one first dose in the range of from 10-30 fig;

(b) at least one second dose in the range of from 20-40 μg, wherein the second dose is higher than the first dose; and then

(c) at least one dose of at least 50 μg.

2. The method of claim 1 , wherein the plurality of doses of the T cell redirecting bispecific therapeutic are administered at a dosing interval of 7 days.

3. The method of claim 1 , wherein the first dose is 20 μg, the second dose is 30 μg and the dose after the second dose is at least 50 μg.

4. The method of claim 1 , wherein two second doses are administered.

5. The method of claim 1 , wherein the TCR has a binding affinity for, and/or a binding half-life for, the YLEPGPVTA (SEQ ID NO:1)-HLA-A2 complex at least double that of a TCR having an extracellular alpha chain sequence SEQ ID No: 2 and an extracellular beta chain sequence SEQ ID No: 3.

6. The method of claim 1 , wherein:

the alpha chain amino acid sequence is (i) and the beta chain-anti-CD3 amino acid sequence is (vii);

the alpha chain amino acid sequence is (i) and the beta chain-anti-CD3 amino acid sequence is (x);

the alpha chain amino acid sequence is (vi) and the beta chain-anti-CD3 amino acid sequence is (ix);

the alpha chain amino acid sequence is (v) and the beta chain-anti-CD3 amino acid sequence is (viii);

the alpha chain amino acid sequence is (vi) and the beta chain-anti-CD3 amino acid sequence is (vii);

the alpha chain amino acid sequence is (i) and the beta chain-anti-CD3 amino acid sequence is (xi);

the alpha chain amino acid sequence is (i) and the beta chain-anti-CD3 amino acid sequence is (xii);

the alpha chain amino acid sequence is (i) and the beta chain-anti-CD3 amino acid sequence is (xiii);

the alpha chain amino acid sequence is (vi) and the beta chain-anti-CD3 amino acid sequence is (xiv);

the alpha chain amino acid sequence is (vi) and the beta chain-anti-CD3 amino acid sequence is (xv);

the alpha chain amino acid sequence is (vi) and the beta chain-anti-CD3 amino acid sequence is (xvi);

the alpha chain amino acid sequence is (v) and the beta chain-anti-CD3 amino acid sequence is (xvii);

the alpha chain amino acid sequence is (v) and the beta chain-anti-CD3 amino acid sequence is (xviii);

the alpha chain amino acid sequence is (v) and the beta chain-anti-CD3 amino acid sequence is (xix);

the alpha chain amino acid sequence is (vi) and the beta chain-anti-CD3 amino acid sequence is (xi);

the alpha chain amino acid sequence is (vi) and the beta chain-anti-CD3 amino acid sequence is (xii); or

the alpha chain amino acid sequence is (vi) and the beta chain-anti-CD3 amino acid sequence is (xiii).

7. The method of claim 6 , wherein the alpha chain amino acid sequence is (v) and the beta chain-anti-CD3 amino acid sequence is (viii).

8. The method of claim 1 , wherein the bispecific therapeutic is administered in combination with one or more anti-cancer therapies.

9. The method of claim 8 , wherein the anti-cancer therapy is durvalumab, tremelimumab, galunisertib and merestinib.

10. The method of claim 9 , wherein the anti-cancer therapy is merestinib and wherein the dose of merestinib is in the range of 40 to 120 mg once daily.

11. The method of claim 1 , wherein the gp100 positive cancer is melanoma.

12. The method of claim 9 , wherein the anti-cancer therapy is merestinib and the dose of merestinib is in the range of 80 to 120 mg once daily.

13. A method of treating gp100 positive cancer in a patient, comprising:

administering to said patient a plurality of doses of a T cell redirecting bispecific therapeutic at a dosing interval of 7 days, wherein the T cell redirecting bispecific therapeutic comprises (1) a TCR that binds to the YLEPGPVTA (SEQ ID NO:1)-HLA-A2 complex, fused to (2) an anti-CD3 antibody, wherein the bispecific therapeutic includes

(a) a TCR alpha chain amino acid sequence as provided in SEQ ID No: 4; and

(b) a TCR beta chain-anti-CD3 sequence as provided in SEQ ID No: 5, and wherein

the method comprises administration of:

(a) at least one first dose of 20 μg;

(b) at least one second dose of 30 μg; and then

(c) at least one dose of at least 50 μg.

14. The method of claim 13 , wherein the gp100 positive cancer is uveal melanoma.