Bispecific antibody against CD3 and CD20 in combination therapy for treating follicular lymphoma

1. A method of treating follicular lymphoma in a human subject, the method comprising administering to the subject a bispecific antibody and an effective amount of rituximab and lenalidomide, wherein the bispecific antibody comprises:

(i) a first binding arm comprising a first antigen-binding region which binds to human CD3ε (epsilon) and comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises the CDR1, CDR2 and CDR3 sequences that are in the VH region sequence of SEQ ID NO: 6, and the VL region comprises the CDR1, CDR2 and CDR3 sequences that are in the VL region sequence of SEQ ID NO: 7; and

(ii) a second binding arm comprising a second antigen-binding region which binds to human CD20 and comprises a VH region and a VL region, wherein the VH region comprises the CDR1, CDR2 and CDR3 sequences that are in the VH region sequence of SEQ ID NO: 13, and the VL region comprises the CDR1, CDR2 and CDR3 sequences that are in the VL region sequence of SEQ ID NO: 14;

wherein the bispecific antibody is administered at a dose of 24 mg, wherein rituximab, lenalidomide, and the bispecific antibody are administered in 28-day cycles, and wherein

(a) the bispecific antibody is administered as follows:

(i) in cycle 1, a priming dose is administered on day 1, an intermediate dose is administered on day 8, and a dose of 24 mg is administered on days 15 and 22;

(ii) in cycles 2 and 3, a dose of 24 mg is administered on days 1, 8, 15, and 22;

(iii) in cycles 4-9, a dose of 24 mg is administered on days 1 and 15; and

(iv) in cycle 10 and subsequent cycles, a dose of 24 mg is administered on day 1;

(b) rituximab is administered on days 1, 8, 15, and 22 in cycle 1, and day 1 in cycles 2-5; and

(c) lenalidomide is administered on days 1-21 in cycles 1-12.

2. The method of claim 1 , wherein (a) the priming dose is 0.16 mg, (b) the intermediate dose is 0.8 mg, or (c) the priming dose is 0.16 mg and the intermediate dose is 0.8 mg.

3. The method of claim 1 , wherein rituximab is administered at a dose of 375 mg/m 2 or equivalent thereof, wherein lenalidomide is administered at a dose of 15 mg in cycle 1 of the 28-day cycles, and wherein lenalidomide is administered at a dose of 20 mg in cycle 2 to cycle 12 of the 28-day cycles.

4. The method of claim 1 , wherein the bispecific antibody is administered subcutaneously.

5. The method of claim 1 , wherein rituximab is administered intravenously and wherein lenalidomide is administered orally.

6. The method of claim 1 , wherein the follicular lymphoma is relapsed and/or refractory follicular lymphoma.

7. The method of claim 6 , wherein the follicular lymphoma is grade 1, 2, or 3a relapsed and/or refractory follicular lymphoma or Stage II, III, or IV relapsed and/or refractory follicular lymphoma.

8. The method of claim 1 , wherein:

(i) the first antigen-binding region of the bispecific antibody comprises a VH region comprising the amino acid sequence of SEQ ID NO: 6, and a VL region comprising the amino acid sequence of SEQ ID NO: 7; and

(ii) the second antigen-binding region of the bispecific antibody comprises a VH region comprising the amino acid sequence of SEQ ID NO: 13, and a VL region comprising the amino acid sequence of SEQ ID NO: 14.

9. The method of claim 1 , wherein the first binding arm of the bispecific antibody is derived from a humanized antibody and comprises a λ light chain constant region comprising the amino acid sequence set forth in SEQ ID NO: 22 and/or wherein the second binding arm of the bispecific antibody is derived from a human antibody and comprises a κ light chain constant region comprising the amino acid sequence set forth in SEQ ID NO: 23.

10. The method of claim 1 , wherein the bispecific antibody is a full-length antibody with a human IgG1 constant region.

11. The method of claim 1 , wherein the bispecific antibody comprises a first heavy chain and a second heavy chain, wherein

(i) in both the first and second heavy chains, the amino acids in the positions corresponding to positions L234, L235, and D265 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 are F, E, and A, respectively, and

(ii) in the first heavy chain, the amino acid in the position corresponding to F405 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 is L, and wherein in the second heavy chain, the amino acid in the position corresponding to K409 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 is R, or vice versa.

12. The method of claim 1 , wherein the bispecific antibody comprises heavy chain constant regions comprising the amino acid sequences of SEQ ID NOs: 19 and 20.

13. The method of claim 1 , wherein the bispecific antibody comprises a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively.

14. The method of claim 1 , wherein the bispecific antibody is epcoritamab, or a biosimilar thereof.

15. A method of treating follicular lymphoma in a human subject, the method comprising administering to the subject a bispecific antibody and an effective amount of rituximab and lenalidomide, wherein the bispecific antibody comprises a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively;

wherein the bispecific antibody is administered at a dose of 24 mg, wherein rituximab, lenalidomide, and the bispecific antibody are administered in 28-day cycles, and wherein:

(a) the bispecific antibody is administered as follows:

(i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg is administered on days 15 and 22;

(ii) in cycles 2 and 3, a dose of 24 mg is administered on days 1, 8, 15, and 22;

(iii) in cycles 4-9, a dose of 24 mg is administered on days 1 and 15; and

(iv) in cycle 10 and subsequent cycles, a dose of 24 mg is administered on day 1;

(b) rituximab is administered on days 1, 8, 15, and 22 in cycle 1, and day 1 in cycles 2-5; and

(c) lenalidomide is administered on days 1-21 in cycles 1-12.

16. A method of treating follicular lymphoma in a human subject, the method comprising administering to the subject a bispecific antibody and an effective amount of rituximab and lenalidomide, wherein the bispecific antibody comprises a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively;

wherein the bispecific antibody is administered at a dose of 48 mg, wherein rituximab, lenalidomide, and the bispecific antibody are administered in 28-day cycles, and wherein:

(a) the bispecific antibody is administered as follows:

(i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 48 mg is administered on days 15 and 22;

(ii) in cycles 2 and 3, a dose of 48 mg is administered on days 1, 8, 15, and 22;

(iii) in cycles 4-9, a dose of 48 mg is administered on days 1 and 15; and

(iv) in cycle 10 and subsequent cycles, a dose of 48 mg is administered on day 1;

(b) rituximab is administered on days 1, 8, 15, and 22 in cycle 1, and day 1 in cycles 2-5; and

(c) lenalidomide is administered on days 1-21 in cycles 1-12.

17. A method of treating follicular lymphoma in a human subject, the method comprising administering to the subject a bispecific antibody and an effective amount of rituximab and lenalidomide, wherein the bispecific antibody comprises:

(i) a first binding arm comprising a first antigen-binding region which binds to human CD3ε (epsilon) and comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises the CDR1, CDR2 and CDR3 sequences that are in the VH region sequence of SEQ ID NO: 6, and the VL region comprises the CDR1, CDR2 and CDR3 sequences that are in the VL region sequence of SEQ ID NO: 7; and

(ii) a second binding arm comprising a second antigen-binding region which binds to human CD20 and comprises a VH region and a VL region, wherein the VH region comprises the CDR1, CDR2 and CDR3 sequences that are in the VH region sequence of SEQ ID NO: 13, and the VL region comprises the CDR1, CDR2 and CDR3 sequences that are in the VL region sequence of SEQ ID NO: 14;

wherein the bispecific antibody is administered at a dose of 48 mg, wherein rituximab, lenalidomide, and the bispecific antibody are administered in 28-day cycles, and wherein

(a) the bispecific antibody is administered as follows:

(i) in cycle 1, a priming dose is administered on day 1, an intermediate dose is administered on day 8, and a dose of 48 mg is administered on days 15 and 22;

(ii) in cycles 2 and 3, a dose of 48 mg is administered on days 1, 8, 15, and 22;

(iii) in cycles 4-9, a dose of 48 mg is administered on days 1 and 15; and

(iv) in cycle 10 and subsequent cycles, a dose of 48 mg is administered on day 1;

(b) rituximab is administered on days 1, 8, 15, and 22 in cycle 1, and day 1 in cycles 2-5; and

(c) lenalidomide is administered on days 1-21 in cycles 1-12.

18. The method of claim 17 , wherein (a) the priming dose is 0.16 mg, (b) the intermediate dose is 0.8 mg, or (c) the priming dose is 0.16 mg and the intermediate dose is 0.8 mg.

19. The method of claim 17 , wherein rituximab is administered at a dose of 375 mg/m 2 or equivalent thereof, wherein lenalidomide is administered at a dose of 15 mg in cycle 1 of the 28-day cycles, and wherein lenalidomide is administered at a dose of 20 mg in cycle 2 to cycle 12 of the 28-day cycles.

20. The method of claim 17 , wherein the bispecific antibody is administered subcutaneously.

21. The method of claim 17 , wherein rituximab is administered intravenously and wherein lenalidomide is administered orally.

22. The method of claim 17 , wherein the follicular lymphoma is relapsed and/or refractory follicular lymphoma.

23. The method of claim 22 , wherein the follicular lymphoma is grade 1, 2, or 3a relapsed and/or refractory follicular lymphoma or Stage II, III, or IV relapsed and/or refractory follicular lymphoma.

24. The method of claim 17 , wherein:

(i) the first antigen-binding region of the bispecific antibody comprises a VH region comprising the amino acid sequence of SEQ ID NO: 6, and a VL region comprising the amino acid sequence of SEQ ID NO: 7; and

(ii) the second antigen-binding region of the bispecific antibody comprises a VH region comprising the amino acid sequence of SEQ ID NO: 13, and a VL region comprising the amino acid sequence of SEQ ID NO: 14.

25. The method of claim 17 , wherein the first binding arm of the bispecific antibody is derived from a humanized antibody and comprises a λ light chain constant region comprising the amino acid sequence set forth in SEQ ID NO: 22 and/or wherein the second binding arm of the bispecific antibody is derived from a human antibody and comprises a κ light chain constant region comprising the amino acid sequence set forth in SEQ ID NO: 23.

26. The method of claim 17 , wherein the bispecific antibody is a full-length antibody with a human IgG1 constant region.

27. The method of claim 17 , wherein the bispecific antibody comprises a first heavy chain and a second heavy chain, wherein

(i) in both the first and second heavy chains, the amino acids in the positions corresponding to positions L234, L235, and D265 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 are F, E, and A, respectively, and

(ii) in the first heavy chain, the amino acid in the position corresponding to F405 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 is L, and wherein in the second heavy chain, the amino acid in the position corresponding to K409 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 is R, or vice versa.

28. The method of claim 17 , wherein the bispecific antibody comprises heavy chain constant regions comprising the amino acid sequences of SEQ ID NOs: 19 and 20.

29. The method of claim 17 , wherein the bispecific antibody comprises a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively.

30. The method of claim 17 , wherein the bispecific antibody is epcoritamab, or a biosimilar thereof.