Anti-HER2 biparatopic antibody-drug conjugates and methods of use
Anti-HER2 biparatopic antibody-drug conjugates (ADCs) in which the drug is an auristatin analogue and is conjugated to the antibody at a low average drug-to-antibody ratio (DAR), and methods of using the ADCs in the treatment of a HER2-expressing cancer. The low average DAR (<3.9) ADCs as described herein have improved tolerability and decreased toxicity as compared to a corresponding ADC having a DAR≥3.9 when administered at the same toxin dose.
1. A composition comprising a plurality of an antibody-drug conjugate comprising an anti-HER2 biparatopic antibody conjugated to an auristatin analogue via a linker,
the anti-HER2 biparatopic antibody comprising:
(i) a first heavy chain (H1) comprising the CDR sequences as set forth in SEQ ID NOs: 39, 40 and 41,
(ii) a second heavy chain (H2) comprising the CDR sequences as set forth in SEQ ID NOs: 67, 68, 69, 70, 71 and 72, and
(iii) a light chain (L1) comprising the CDR sequences as set forth in SEQ ID NOs: 27, 28 and 29, and
the auristatin analogue and linker having the structure:
wherein A-S— is the point of attachment to the anti-HER2 biparatopic antibody; and
wherein the composition has an average drug-to-antibody ratio (DAR) of between 1.8 and 2.5 and the composition comprises between about 10% and about 25% DAR0 species of the antibody-drug conjugate.
2. The composition according to claim 1 , wherein the average DAR is about 2.0.
3. The composition according to claim 1 , wherein:
(i) the H1 comprises the VH sequence as set forth in SEQ ID NO: 38,
(ii) the H2 comprises the VH sequence as set forth in SEQ ID NO: 66 and the VL sequence as set forth in SEQ ID NO: 65, and
(iii) the L1 comprises the VL sequence as set forth in SEQ ID NO: 26.
4. The composition according to claim 1 , wherein the H1 comprises the sequence as set forth in SEQ ID NO: 36, the H2 comprises the sequence as set forth in SEQ ID NO: 63, and the L1 comprises the sequence as set forth in SEQ ID NO: 24.
5. The composition according to claim 1 , wherein the H1 consists of the sequence as set forth in SEQ ID NO: 36, the H2 consists of the sequence as set forth in SEQ ID NO: 63, and the L1 consists of the sequence as set forth in SEQ ID NO: 24.
6. The composition according to claim 5 , wherein the low average DAR is an average DAR of about 2.0.
7. The composition according to claim 1 , wherein the composition comprises between about 15% and about 25% DAR0 species of the antibody-drug conjugate.
8. The composition according to claim 1 , wherein the composition comprises between about 0% and about 10% DAR6 or greater species of the antibody-drug conjugate.
9. The composition according to claim 3 , wherein the composition comprises between about 15% and about 25% DAR0 species of the antibody-drug conjugate.
10. The composition according to claim 4 , wherein the composition comprises between about 15% and about 25% DAR0 species of the antibody-drug conjugate.
11. The composition according to claim 5 , wherein the composition comprises between about 15% and about 25% DAR0 species of the antibody-drug conjugate.
12. The composition according to claim 3 , wherein the average DAR is about 2.0.
13. The composition according to claim 4 , wherein the average DAR is about 2.0.
14. A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable carrier or excipient.
15. A pharmaceutical composition comprising the composition of claim 3 and a pharmaceutically acceptable carrier or excipient.
16. A pharmaceutical composition comprising the composition of claim 4 and a pharmaceutically acceptable carrier or excipient.
17. A pharmaceutical composition comprising the composition of claim 5 and a pharmaceutically acceptable carrier or excipient.