IP Library › Granted Patent US 12,115,227

Granted Patent B2

US 12,115,227 · App. 16/069,391 · Granted Oct 15, 2024

Formulation for antibody and drug conjugate thereof

Inventors: Lene Schantz Harlow (Frederiksberg, DK); Timothy Warren Paul (Bloomington, IN); Brendan M. Mayhugh (Bloomington, IN); Kelly Ann Roby (Bloomington, IN); Gregory Allan Sacha (Bargersville, IN); Xiaona Jing (Riehen, CH); Andrew Hagarman (Durham, NC); Cale Halbleib (Apex, NC)

Assignee: GENMAB A/S

A61K47/6849 A61K9/0019 A61K9/19 A61K38/07 A61K39/39591 A61K47/183 A61K47/26 A61K47/6803 A61K47/6811 A61K47/6921 C07K16/2863 A61K2039/505 C07K2317/24 C07K2317/31 C07K2317/34 C07K2317/622 C07K2317/73

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Patent No.: US 12,115,227
App. No.: 16/069,391
Granted: Oct 15, 2024
Kind: B2

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Abstract

Disclosed herein are surfactant free antibody and antibody-drug-conjugate (ADC) formulations for anti-AXL antibodies and ADCs, including aqueous formulations, lyophilized formulations, and reconstituted formulations, as well as related processes and uses. The formulations are particularly suitable for an anti-AXL ADC based on an auristatin or DM1 derivative or other similarly hydrophobic drugs. Some formulations comprise histidine and mannitol.

Claims (262)

1. A lyophilized formulation of an anti-AXL antibody-drug conjugate (AXL-ADC), the lyophilized formulation obtainable or obtained by lyophilizing an aqueous formulation comprising the AXL-ADC and one or more excipients, wherein the aqueous formulation is free of any surfactant, wherein the drug moiety of the AXL-ADC is a cytotoxic agent, and wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region and a VL region selected from the group consisting of:

(a) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 39, the sequence GAS, and SEQ ID No: 40, respectively;

(b) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 46, 47, and 48, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 49, the sequence AAS, and SEQ ID No: 50, respectively;

(c) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 114, 115, and 116, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 117, the sequence DAS, and SEQ ID No: 118, respectively;

(d) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 51, 52, and 53, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 55, the sequence GAS, and SEQ ID No: 56, respectively;

(e) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 51, 52, and 54, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 55, the sequence GAS, and SEQ ID No: 56, respectively;

(f) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 57, 58, and 59, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 60, the sequence GAS, and SEQ ID No: 61, respectively;

(g) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 62, 63, and 64, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 65, the sequence GAS, and SEQ ID No: 66, respectively;

(h) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 67, 68, and 69, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 70, the sequence GAS, and SEQ ID No: 71, respectively;

(i) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 72, 73, and 75, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 76, the sequence ATS, and SEQ ID No: 77, respectively;

(j) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 72, 74, and 75, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 76, the sequence ATS, and SEQ ID No: 77, respectively;

(k) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 78, 79, and 80, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 81, the sequence AAS, and SEQ ID No: 82, respectively;

(l) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 83, 84, and 85, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 86, the sequence GAS, and SEQ ID No: 87, respectively;

(m) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 88, 89, and 90, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 91, the sequence GAS, and SEQ ID No: 92, respectively;

(n) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 96, the sequence GAS, and SEQ ID No: 97, respectively;

(o) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 101, the sequence DAS, and SEQ ID No: 102, respectively;

(p) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 103, 104, and 105, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 106, the sequence GAS, and SEQ ID No: 107, respectively;

(q) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 108, 109, and 110, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 112, the sequence AAS, and SEQ ID No: 113, respectively;

(r) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 108, 109, and 111, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 112, the sequence AAS, and SEQ ID No: 113, respectively; and

(s) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 41, 42, and 43, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 44, the sequence AAS, and SEQ ID No: 45, respectively.

2. The lyophilized formulation of claim 1 , wherein the aqueous formulation comprises:

(a) a buffer providing for a pH of between about 5 and about 7 in the aqueous formulation;

(b) at least one bulking agent; and

3. The lyophilized formulation of claim 1 ,

wherein the aqueous formulation comprises a buffer selected from the group consisting of histidine, citrate, 2-(N-morpholino) ethanesulfonic acid (MES), succinate, glycolate, carbonic acid and phosphate, and a combination of any thereof;

wherein the pH of the aqueous formulation is in a range from about 5 to about 7; and

wherein the aqueous formulation comprises a buffer at a concentration of about 5 mM to about 100 mM.

4. The lyophilized formulation of claim 1 , comprising a bulking agent selected from the group consisting of mannitol, glycine, and a combination thereof.

5. The lyophilized formulation of claim 1 , wherein the aqueous formulation comprises a bulking agent at a concentration of about 1% (w/v) to about 5% (w/v), or at a concentration of about 50 mM to about 300 mM.

6. The lyophilized formulation of claim 1 , comprising a non-reducing sugar selected from the group consisting of sucrose, trehalose, and a combination thereof.

7. The lyophilized formulation of claim 1 , wherein the aqueous formulation comprises a non-reducing sugar at a concentration of about 0.5% (w/v) to about 7% (w/v), or a concentration of about 15 mM to about 200 mM.

8. The lyophilized formulation of claim 1 , wherein the AXL-ADC concentration in the aqueous formulation is from about 5 mg/mL to about 30 mg/mL.

9. The lyophilized formulation of claim 1 , wherein the pH of the aqueous formulation is in a range from about 5.5 to about 6.5.

10. A lyophilized formulation obtainable or obtained by lyophilizing an aqueous formulation having a pH of about 5 to about 7 and comprising

(a) about 5 mg/mL to about 30 mg/mL of an anti-AXL antibody-drug conjugate (AXL-ADC);

(b) about 10 mM to about 50 mM histidine;

(d) about 150 mM to about 180 mM mannitol or glycine,

wherein the drug moiety of the AXL-ADC is a cytotoxic agent, and the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region and a VL region selected from the group consisting of:

11. A pharmaceutical formulation having a pH of about 5 to about 7 and comprising, in aqueous solution:

(a) about 5 mg/mL to about 30 mg/mL of an anti-AXL antibody-drug conjugate (AXL-ADC);

(b) about 10 mM to about 50 mM histidine;

(d) about 50 mM to about 300 mM mannitol or glycine,

(c) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 51, 52, and 54, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 55, the sequence GAS, and SEQ ID No: 56, respectively;

12. The pharmaceutical formulation of claim 11 , having a pH in the range of about 5.5 to about 6.5 and comprising:

(a) about 9 mg/mL to about 11 mg/mL AXL-ADC;

(b) about 20 mM to about 40 mM histidine;

(d) about 150 mM to about 180 mM mannitol;

wherein the formulation is free of any surfactant.

13. An aqueous formulation of an anti-AXL antibody, comprising one or more pharmaceutically acceptable excipients, wherein the aqueous formulation is free of any surfactant, and wherein the anti-AXL antibody comprises a VH region and a VL region selected from the group consisting of:

14. The aqueous formulation of claim 13 , wherein the formulation comprises a buffer and at least one stabilizer, wherein the pH of the aqueous formulation is between about 5 and about 7.

15. The aqueous formulation of claim 13 , comprising a buffer selected from the group consisting of histidine, citrate, MES, phosphate, carbonic acid, succinate, glycolate, and a combination of any thereof, wherein

the buffer is at a concentration of about 10 mM to about 50 mM, and

the pH of the aqueous formulation is in a range of about 5.5 to about 6.5.

16. The aqueous formulation of claim 13 , comprising a stabilizer selected from the group consisting of mannitol, sucrose and trehalose, wherein the stabilizer is present at a concentration of about 20 mM to about 400 mM, or a concentration of about 0.4% (w/v) to about 7% (w/v).

17. The aqueous formulation of claim 13 , which is free of any one or more of arginine, glycine, glutamic acid, sorbitol, trehalose, sucrose and sodium chloride.

18. The aqueous formulation of claim 13 , wherein the antibody concentration is from about 5 mg/mL to about 40 mg/mL.

19. The aqueous formulation of claim 14 , wherein the formulation comprises

(a) about 5 mg/mL to about 40 mg/mL of an anti-AXL antibody;

(b) about 10 mM to about 50 mM histidine; and

20. A frozen aqueous formulation of an anti-AXL antibody,

obtained or obtainable by freezing the aqueous formulation of claim 13 .

21. A lyophilized formulation of an anti-AXL antibody-drug conjugate (AXL-ADC), the lyophilized formulation obtainable or obtained by lyophilizing an aqueous formulation comprising the AXL-ADC and one or more excipients, wherein the aqueous formulation is free of any surfactant, wherein the AXL-ADC binds to an epitope on AXL which is recognized by any of the antibodies defined in claim 13 .

22. The lyophilized formulation of claim 1 , wherein the AXL-ADC binds to an epitope within the Ig1-like domain of AXL, the epitope comprising one or more amino acids corresponding to positions L121 to Q129 or T112 to Q124 of human AXL; an epitope within the Ig2-like domain of AXL, the epitope comprising the amino acids corresponding to position D170 or the combination of D179 and one or more amino acids corresponding to positions T182 to R190 of human AXL; or an epitope within the FN1-like domain of human AXL, the epitope comprising one or more amino acids corresponding to positions Q272 to A287 and G297 to P301 of human AXL.

23. The lyophilized formulation of claim 1 , wherein the antibody moiety of the AXL-ADC comprises a heavy chain of an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.

24. The lyophilized formulation of claim 1 , wherein the antibody moiety of the AXL-ADC is a full-length monoclonal antibody.

25. A lyophilized formulation obtainable or obtained by lyophilizing an aqueous formulation comprising

about 9 mg/mL to about 11 mg/mL of an anti-AXL antibody-drug conjugate (AXL-ADC), and pharmaceutically acceptable excipients comprising:

about 30 mM histidine buffer providing for a pH from about 5 to about 7;

about 88 mM sucrose; and

about 165 mM mannitol;

wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region and a VL region selected from the group consisting of:

(b) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 46, 47, and 48, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 49, the sequence AAS, and SEQ ID No: 50, respectively;

(c) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 114, 115, and 116, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 117, the sequence DAS, and SEQ ID No: 118, respectively;

(d) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 51, 52, and 53, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 55, the sequence GAS, and SEQ ID No: 56, respectively;

(e) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 51, 52, and 54, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 55, the sequence GAS, and SEQ ID No: 56, respectively;

(f) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 57, 58, and 59, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 60, the sequence GAS, and SEQ ID No: 61, respectively;

(g) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 62, 63, and 64, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 65, the sequence GAS, and SEQ ID No: 66, respectively;

(h) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 67, 68, and 69, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 70, the sequence GAS, and SEQ ID No: 71, respectively;

(i) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 72, 73, and 75, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 76, the sequence ATS, and SEQ ID No: 77, respectively;

(j) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 72, 74, and 75, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 76, the sequence ATS, and SEQ ID No: 77, respectively;

(k) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 78, 79, and 80, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 81, the sequence AAS, and SEQ ID No: 82, respectively;

(l) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 83, 84, and 85, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 86, the sequence GAS, and SEQ ID No: 87, respectively;

(m) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 88, 89, and 90, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 91, the sequence GAS, and SEQ ID No: 92, respectively;

(n) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 96, the sequence GAS, and SEQ ID No: 97, respectively;

(o) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 101, the sequence DAS, and SEQ ID No: 102, respectively;

(p) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 103, 104, and 105, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 106, the sequence GAS, and SEQ ID No: 107, respectively;

(q) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 108, 109, and 110, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 112, the sequence AAS, and SEQ ID No: 113, respectively;

(r) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 108, 109, and 111, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 112, the sequence AAS, and SEQ ID No: 113, respectively; and

(s) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 41, 42, and 43, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 44, the sequence AAS, and SEQ ID No: 45, respectively;

wherein the AXL-ADC comprises a mc-vc-PAB linker and MMAE.

26. An aqueous formulation suitable for preparing a lyophilized formulation of an anti-AXL antibody-drug conjugate (AXL-ADC) and having a pH of about 5 to about 7, comprising

(a) about 7 mg/mL to about 20 mg/mL of an AXL-ADC;

(b) about 5 mM to about 100 mM histidine;

(d) about 150 mM to about 180 mM mannitol,

27. The aqueous formulation of claim 26 , wherein the antibody moiety of the AXL-ADC comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 39, the sequence GAS, and SEQ ID No: 40, respectively.

28. The aqueous formulation of claim 26 , wherein the AXL-ADC comprises a mc-vc-PAB linker and MMAE.

29. A pharmaceutically acceptable liquid formulation obtained by reconstituting the lyophilized formulation of claim 25 in a sterile aqueous diluent.

30. The liquid formulation of claim 29 , having a pH of about 5 to about 7, and comprising about 5 mg/mL to about 30 mg/mL of the AXL-ADC; about 10 mM to about 50 mM histidine; about 15 mM to about 120 mM sucrose; and about 50 mM to about 300 mM mannitol or glycine, wherein the weight ratio of mannitol to sucrose is at least about 1.

31. The lyophilized formulation of claim 1 , wherein the AXL-ADC comprises a cleavable linker selected from the group consisting of: N-succinimydyl 4-(2-pyridyldithio)-pentanoate (SSP), maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PAB), and AV-1 K-lock valine-citrulline.

32. The lyophilized formulation of claim 1 , wherein the cytotoxic agent is monomethylauristatin E (MMAE) or monomethylauristatin F (MMAF).

33. The lyophilized formulation of claim 1 , wherein the AXL-ADC comprises a VH region and a VL region selected from the group consisting of:

(a) a VH region comprising SEQ ID No: 1 and a VL region comprising SEQ ID No: 2;

(b) a VH region comprising SEQ ID No: 5 and a VL region comprising SEQ ID No: 6;

(d) a VH region comprising SEQ ID No: 7 and a VL region comprising SEQ ID No: 9;

(e) a VH region comprising SEQ ID No: 10 and a VL region comprising SEQ ID No: 11;

(f) a VH region comprising SEQ ID No: 16 and a VL region comprising SEQ ID No: 18;

(g) a VH region comprising SEQ ID No: 25 and a VL region comprising SEQ ID No: 26;

(h) a VH region comprising SEQ ID No: 31 and a VL region comprising SEQ ID No: 33;

(i) a VH region comprising SEQ ID No: 3 and a VL region comprising SEQ ID No: 4;

(j) a VH region comprising SEQ ID No:8 and a VL region comprising SEQ ID No:9;

(k) a VH region comprising SEQ ID No: 12 and a VL region comprising SEQ ID No:13;

(l) a VH region comprising SEQ ID No: 14 and a VL region comprising SEQ ID No: 15;

(m) a VH region comprising SEQ ID No: 17 and a VL region comprising SEQ ID No:18;

(n) a VH region comprising SEQ ID No: 19 and a VL region comprising SEQ ID No:20;

(o) a VH region comprising SEQ ID No:21 and a VL region comprising SEQ ID No:22;

(p) a VH region comprising SEQ ID No:23 and a VL region comprising SEQ ID No:24;

(q) a VH region comprising SEQ ID No:27 and a VL region comprising SEQ ID No:28;

(r) a VH region comprising SEQ ID No:29 and a VL region comprising SEQ ID No:30; and

(s) a VH region comprising SEQ ID No:32 and a VL region comprising SEQ ID No: 33.

34. The lyophilized formulation of claim 1 , wherein the cytotoxic agent is an auristatin.

35. The lyophilized formulation of claim 10 , wherein the cytotoxic agent is an auristatin.

36. The lyophilized formulation of claim 11 , wherein the cytotoxic agent is an auristatin.

37. The lyophilized formulation of claim 26 , wherein the cytotoxic agent is an auristatin.

38. The lyophilized formulation of claim 1 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 36, 37, and 38, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 39, the sequence GAS, and SEQ ID No: 40, respectively.

39. The lyophilized formulation of claim 1 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 46, 47, and 48, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 49, the sequence AAS, and SEQ ID No: 50, respectively.

40. The lyophilized formulation of claim 1 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 114, 115, and 116, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 117, the sequence DAS, and SEQ ID No: 118, respectively.

41. The lyophilized formulation of claim 1 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 51, 52, and 54, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 55, the sequence GAS, and SEQ ID No: 56, respectively.

42. The lyophilized formulation of claim 1 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 57, 58, and 59, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 60, the sequence GAS, and SEQ ID No: 61, respectively.

43. The lyophilized formulation of claim 1 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 72, 74, and 75, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 76, the sequence ATS, and SEQ ID No: 77, respectively.

44. The lyophilized formulation of claim 1 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 96, the sequence GAS, and SEQ ID No: 97, respectively.

45. The lyophilized formulation of claim 1 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 101, the sequence DAS, and SEQ ID No: 102, respectively.

46. The lyophilized formulation of claim 1 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 108, 109, and 111, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 112, the sequence AAS, and SEQ ID No: 113, respectively.

47. The lyophilized formulation of claim 10 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 36, 37, and 38, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 39, the sequence GAS, and SEQ ID No: 40, respectively.

48. The lyophilized formulation of claim 10 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 46, 47, and 48, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 49, the sequence AAS, and SEQ ID No: 50, respectively.

49. The lyophilized formulation of claim 10 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 114, 115, and 116, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 117, the sequence DAS, and SEQ ID No: 118, respectively.

50. The lyophilized formulation of claim 10 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 51, 52, and 54, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 55, the sequence GAS, and SEQ ID No: 56, respectively.

51. The lyophilized formulation of claim 10 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 57, 58, and 59, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 60, the sequence GAS, and SEQ ID No: 61, respectively.

52. The lyophilized formulation of claim 10 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 72, 74, and 75, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 76, the sequence ATS, and SEQ ID No: 77, respectively.

53. The lyophilized formulation of claim 10 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 96, the sequence GAS, and SEQ ID No: 97, respectively.

54. The lyophilized formulation of claim 10 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 101, the sequence DAS, and SEQ ID No: 102, respectively.

55. The lyophilized formulation of claim 10 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 108, 109, and 111, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 112, the sequence AAS, and SEQ ID No: 113, respectively.

56. The pharmaceutical formulation of claim 11 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 36, 37, and 38, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 39, the sequence GAS, and SEQ ID No: 40, respectively.

57. The pharmaceutical formulation of claim 11 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 46, 47, and 48, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 49, the sequence AAS, and SEQ ID No: 50, respectively.

58. The pharmaceutical formulation of claim 11 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 114, 115, and 116, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 117, the sequence DAS, and SEQ ID No: 118, respectively.

59. The pharmaceutical formulation of claim 11 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 51, 52, and 54, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 55, the sequence GAS, and SEQ ID No: 56, respectively.

60. The pharmaceutical formulation of claim 11 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 57, 58, and 59, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 60, the sequence GAS, and SEQ ID No: 61, respectively.

61. The pharmaceutical formulation of claim 11 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 72, 74, and 75, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 76, the sequence ATS, and SEQ ID No: 77, respectively.

62. The pharmaceutical formulation of claim 11 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 96, the sequence GAS, and SEQ ID No: 97, respectively.

63. The pharmaceutical formulation of claim 11 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 101, the sequence DAS, and SEQ ID No: 102, respectively.

64. The pharmaceutical formulation of claim 11 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 108, 109, and 111, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 112, the sequence AAS, and SEQ ID No: 113, respectively.

65. The aqueous formulation of claim 13 , wherein the anti-AXL antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 36, 37, and 38, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 39, the sequence GAS, and SEQ ID No: 40, respectively.

66. The aqueous formulation of claim 13 , wherein the anti-AXL antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 46, 47, and 48, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 49, the sequence AAS, and SEQ ID No: 50, respectively.

67. The aqueous formulation of claim 13 , wherein the anti-AXL antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 114, 115, and 116, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 117, the sequence DAS, and SEQ ID No: 118, respectively.

68. The aqueous formulation of claim 13 , wherein the anti-AXL antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 51, 52, and 54, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 55, the sequence GAS, and SEQ ID No: 56, respectively.

69. The aqueous formulation of claim 13 , wherein the anti-AXL antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 57, 58, and 59, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 60, the sequence GAS, and SEQ ID No: 61, respectively.

70. The aqueous formulation of claim 13 , wherein the anti-AXL antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 72, 74, and 75, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 76, the sequence ATS, and SEQ ID No: 77, respectively.

71. The aqueous formulation of claim 13 , wherein the anti-AXL antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 96, the sequence GAS, and SEQ ID No: 97, respectively.

72. The aqueous formulation of claim 13 , wherein the anti-AXL antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 101, the sequence DAS, and SEQ ID No: 102, respectively.

73. The aqueous formulation of claim 13 , wherein the anti-AXL antibody comprises a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 108, 109, and 111, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 112, the sequence AAS, and SEQ ID No: 113, respectively.

74. The lyophilized formulation of claim 25 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 36, 37, and 38, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 39, the sequence GAS, and SEQ ID No: 40, respectively.

75. The lyophilized formulation of claim 25 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 46, 47, and 48, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 49, the sequence AAS, and SEQ ID No: 50, respectively.

76. The lyophilized formulation of claim 25 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 114, 115, and 116, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 117, the sequence DAS, and SEQ ID No: 118, respectively.

77. The lyophilized formulation of claim 25 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 51, 52, and 54, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 55, the sequence GAS, and SEQ ID No: 56, respectively.

78. The lyophilized formulation of claim 25 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 57, 58, and 59, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 60, the sequence GAS, and SEQ ID No: 61, respectively.

79. The lyophilized formulation of claim 25 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 72, 74, and 75, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 76, the sequence ATS, and SEQ ID No: 77, respectively.

80. The lyophilized formulation of claim 25 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 96, the sequence GAS, and SEQ ID No: 97, respectively.

81. The lyophilized formulation of claim 25 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 101, the sequence DAS, and SEQ ID No: 102, respectively.

82. The lyophilized formulation of claim 25 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 108, 109, and 111, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 112, the sequence AAS, and SEQ ID No: 113, respectively.

83. The aqueous formulation of claim 26 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos: 36, 37, and 38, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 39, the sequence GAS, and SEQ ID No: 40, respectively.

84. The aqueous formulation of claim 26 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 46, 47, and 48, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 49, the sequence AAS, and SEQ ID No: 50, respectively.

85. The aqueous formulation of claim 26 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 114, 115, and 116, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 117, the sequence DAS, and SEQ ID No: 118, respectively.

86. The aqueous formulation of claim 26 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 51, 52, and 54, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 55, the sequence GAS, and SEQ ID No: 56, respectively.

87. The aqueous formulation of claim 26 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 57, 58, and 59, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 60, the sequence GAS, and SEQ ID No: 61, respectively.

88. The aqueous formulation of claim 26 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 72, 74, and 75, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 76, the sequence ATS, and SEQ ID No: 77, respectively.

89. The aqueous formulation of claim 26 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 96, the sequence GAS, and SEQ ID No: 97, respectively.

90. The aqueous formulation of claim 26 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 101, the sequence DAS, and SEQ ID No: 102, respectively.

91. The aqueous formulation of claim 26 , wherein the antibody moiety of the AXL-ADC comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID Nos.: 108, 109, and 111, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 112, the sequence AAS, and SEQ ID No: 113, respectively.

Assignments (3)

SECURITY INTEREST Recorded Dec 15, 2025

From: GENMAB A/S; GENMAB B.V.; GENMAB HOLDING B.V.

To: MORGAN STANLEY SENIOR FUNDING, INC.

Reel/Frame 073933/0597 →

NOTICE OF GRANT OF SECURITY INTEREST IN PATENTS Recorded Dec 15, 2025

From: GENMAB A/S; GENMAB B.V.; GENMAB HOLDING B.V.

To: WILMINGTON TRUST, NATIONAL ASSOCIATION

Reel/Frame 073949/0722 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 12, 2021

From: HARLOW, LENE SCHANTZ; PAUL, TIMOTHY WARREN; MAYHUGH, BRENDAN M.; ROBY, KELLY ANN; SACHA, GREGORY ALLAN; JING, XIAONA; HAGARMAN, ANDREW; HALBLEIB, CALE

To: GENMAB A/S

Reel/Frame 056823/0084 →

Continuity (2)

Provisional Application 62278217 · Jan 13, 2016

Related Publication 20190030180A1 · Jan 31, 2019