Anti-AXL antibodies, antibody fragments and their immunoconjugates and uses thereof

1. An antibody or antibody fragment that specifically binds to Axl protein, said antibody or antibody fragment comprising a heavy chain variable region including three complementarity determining regions having H1, H2, and H3 sequences, and a light chain variable region including three complementarity determining regions having L1, L2, and L3 sequences, wherein:

(a) the H1 sequence is X 1 GX 2 X 3 MX 4 (SEQ ID NO: 1);

(b) the H2 sequence is LIKX 5 SNGGTX 6 YNQKFKG (SEQ ID NO: 2); and

(c) the H3 sequence is GX 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 DYX 15 X 16 (SEQ ID NO: 3),

wherein

X 1 is T or A or W,

X 2 is H or A,

X 3 is T,

X 4 is N,

X 5 is P,

X 6 is S,

X 7 is H,

X 8 is Y,

X 9 is E,

X 10 is S,

X 11 is Y,

X 12 is E,

X 13 is A,

X 14 is M,

X 15 is W, and

X 16 is G, and

(d) the L1 sequence is KASQDX 17 X 18 SX 19 VX 20 (SEQ ID NO: 4);

(e) the L2 sequence is X 21 X 22 X 23 TRX 24 T (SEQ ID NO: 5); and

(f) the L3 sequence is QEX 25 X 26 SX 27 X 28 X 29 X 30 (SEQ ID NO: 6),

wherein

X 17 is V,

X 18 is S or V,

X 19 is A,

X 20 is A,

X 21 is W,

X 22 is Q,

X 23 is D,

X 24 is H,

X 25 is H,

X 26 is F,

X 27 is T or P,

X 28 is P,

X 29 is L, and

X 30 is T or R;

wherein the isolated antibody or antibody fragment has a higher binding affinity to human Axl protein in a tumor microenvironment of pH 5.8 to 7.0 in comparison with a non-tumor microenvironment of pH 7.2 to 7.8; and

the antibody or antibody fragment has a ratio of binding affinity to the human Axl protein in the tumor microenvironment to a binding affinity to the human Axl protein in the non-tumor microenvironment of at least 1.5:1.

2. The antibody or antibody fragment of claim 1 , wherein the antibody or antibody fragment is a chimeric antibody, a multispecific antibody, or a humanized antibody.

3. The antibody or antibody fragment of claim 1 , wherein X 1 is W, X 2 is A, X 18 is V, X 27 is P, and X 30 is T.

4. The antibody or antibody fragment of claim 1 , wherein X 1 is T, X 2 is H, X 18 is V, X 27 is T, and X 30 is T.

5. The antibody or antibody fragment of claim 1 , wherein X 1 is T, X 2 is A, X 18 is S, X 27 is T, and X 30 is T.

6. The antibody or antibody fragment of claim 1 , wherein X 1 is W, X 2 is A, X 18 is S, X 27 is P, and X 30 is T.

7. The antibody or antibody fragment of claim 1 , wherein the antibody or antibody fragment has a ratio of binding affinity to the Axl protein at a value of a condition in a tumor microenvironment and a binding affinity to the Axl protein at a different value of the same condition in a non-tumor microenvironment of at least about 2:1, at least about 3:1, at least about 4:1, at least about 5:1, at least about 6:1, at least about 7:1, at least about 8:1, at least about 9:1, at least about 10:1, at least about 20:1, at least about 30:1, at least about 50:1, at least about 70:1, or at least about 100:1.

8. An immunoconjugate comprising the antibody or antibody fragment of claim 1 .

9. The immunoconjugate of claim 8 , wherein the immunoconjugate comprises at least one agent selected from a chemotherapeutic agent, a radioactive atom, a cytostatic agent and a cytotoxic agent.

10. The immunoconjugate of claim 9 , comprising at least two of said agents.

11. The immunoconjugate of claim 9 , wherein the antibody or antibody fragment and the at least one agent are covalently bonded to a linker molecule.

12. The immunoconjugate of claim 9 , wherein the at least one agent is selected from maytansinoids, auristatins, dolastatins, calicheamicin, pyrrolobenzodiazepines, and anthracyclines.

13. A pharmaceutical composition comprising the antibody or antibody fragment of claim 1 and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition of claim 13 , further comprising a tonicity agent.

15. A method of treating cancer comprising a step of administering the pharmaceutical composition of claim 13 to a patient with an Axl-expressing cancer.

16. A pharmaceutical composition comprising the immunoconjugate of claim 9 and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition of claim 16 , further comprising a tonicity agent.

18. A method of treating cancer comprising a step of administering the pharmaceutical composition of claim 16 to a patient with an Axl-expressing cancer.

19. A method of treating cancer comprising a step of administering the antibody or antibody fragment of claim 1 to a patient with an Axl-expressing cancer.

20. A method of treating cancer comprising a step of administering the immunoconjugate of claim 8 to a patient with an Axl-expressing cancer.