Anti-cMET antibody drug conjugates and therapeutic uses thereof

Abstract

The present application relates, inter alia, to anti-cMET antibody drug conjugates ("ADC") ("pH-ADC") having lower target-specific binding at lower pH relative to physiological pH; a pharmaceutical composition including the pH-ADC; a method for preparing the pH-ADC; methods of selecting a specific patient population for cancer treatment with an anti-cMET pH-ADC; the present invention relates to pH-ADCs, and methods of using the pH-ADCs in the treatment of cancer, including cMET + / cMET-expressing or overexpressing cancers, in particular non-small cell lung cancer ("NSCLC"), including cMET + / cMET-expressing or overexpressing cMET.

Claims

1. A method of treating a cMET-positive, cMET-overexpressing, and / or MET-amplified solid tumor cancer, the method comprising administering to a human subject having the cancer an effective amount of an anti-cMET antibody drug conjugate (ADC) for a period of time sufficient to provide a therapeutic benefit, wherein the antibody component of the ADC exhibits cMET-specific pH-dependent binding, wherein the antibody comprises heavy and light chain CDRs present in the amino acid sequences of one of the following pairs: SEQ ID NOs: 15 and 16; SEQ ID NOs: 5 and 6; SEQ ID NOs: 7 and 8; SEQ ID NOs: 9 and 10; SEQ ID NOs: 11 and 12; SEQ ID NOs: 13 and 14; SEQ ID NOs: 17 and 18; SEQ ID NOs: 19 and 20; SEQ ID NOs: 21 and 22; SEQ ID NOs: 23 and 24; SEQ ID NOs: 25 and 26; SEQ ID NOs: 27 and 28; SEQ ID NOs: 29 and 30; SEQ ID NOs: 31 and 32; and SEQ ID NOs: NOs: 33 and 34; optionally wherein the CDRs are determined using the Kabat or IMGT system.

2. A method of treating a cMET-positive solid tumor cancer having low or intermediate expression of cMET, the method comprising administering to a human subject previously identified or selected as having the cancer an effective amount of an anti-cMET antibody drug conjugate (ADC) for a period of time sufficient to provide a therapeutic benefit, wherein the antibody component of the ADC exhibits cMET-specific pH-dependent binding, and optionally wherein the antibody comprises heavy and light chain CDRs present in the amino acid sequences set forth in one of the following pairs: SEQ ID NOs: 15 and 16; SEQ ID NOs: 5 and 6; SEQ ID NOs: 7 and 8; SEQ ID NOs: 9 and 10; SEQ ID NOs: 11 and 12; SEQ ID NOs: 13 and 14; SEQ ID NOs: 17 and 18; SEQ ID NOs: 19 and 20; SEQ ID NOs: 21 and 22; SEQ ID NOs: 23 and 24; SEQ ID NOs: 25 and 26; SEQ ID NOs: 27 and 28; SEQ ID NOs: 29 and 30; SEQ ID NOs: 31 and 32; SEQ ID NOs: 33 and 34; SEQ ID NOs: 35 and 36; SEQ ID NOs: 37 and 38; SEQ ID NOs: 39 and 40; SEQ ID NOs: 41 and 42; SEQ ID NOs: 43 and 44; SEQ ID NOs: 45 and 46; SEQ ID NOs: 47 and 48; SEQ ID NOs: 49 and 50; SEQ ID NOs: 51 and 52; SEQ ID NOs: 53 and 54; SEQ ID NOs: 55 and 56; SEQ ID NOs: 57 and 58; SEQ ID NOs: 59 and 60; SEQ ID ID NOs: 31 and 32; and SEQ ID NOs: 33 and 34; optionally wherein the CDRs are determined using the Kabat or IMGT system.

3. A method of treating a cMET-positive solid tumor cancer having a cMET immunohistochemistry score of 1+, 2+, or 3+ and / or an H-score of at least about 50 to 300, the method comprising administering to a human subject previously identified or selected as having the cancer an effective amount of an anti-cMET antibody drug conjugate (ADC) for a period of time sufficient to provide a therapeutic benefit, wherein the antibody component of the ADC exhibits cMET-specific pH-dependent binding, wherein the antibody comprises heavy and light chain CDRs present in the amino acid sequences set forth in one of the following pairs: SEQ ID NOs: 15 and 16; SEQ ID NOs: 5 and 6; SEQ ID NOs: 7 and 8; SEQ ID NOs: 9 and 10; SEQ ID NOs: 11 and 12; SEQ ID NOs: 13 and 14; SEQ ID NOs: 17 and 18; SEQ ID NOs: 19 and 20; SEQ ID NOs: 21 and 22; SEQ ID NOs: 23 and 24; SEQ ID NOs: 25 and 26; SEQ ID NOs: 27 and 28. NOs: 27 and 28; SEQ ID NOs: 29 and 30; SEQ ID NOs: 31 and 32; and SEQ ID NOs: 33 and 34; optionally wherein the CDRs are determined using the Kabat or IMGT system.

4. The method of claim 3, wherein the heavy chain and the light chain of the antibody component of the ADC comprise the heavy chain CDRs and the light chain CDRs present in SEQ ID NO: 15 and SEQ ID NO: 16, respectively, and / or wherein the heavy chain comprises the sequence shown in SEQ ID NO: 15 and the light chain comprises the sequence shown in SEQ ID NO: 16, and wherein the cancer is non-small cell lung cancer ("NSCLC"), optionally selected from non-squamous NSCLC, squamous NSCLC, and otherwise unspecified NSCLC.

5. The method of claim 3 or 4, wherein a biopsy of a tumor from the cancer and / or the whole tumor itself comprises at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90% or 100% of cancer cells having a cMET expression level of at least 1+, 2+ or 3+ as scored by an applicable and / or regulatory agency approved immunohistochemistry (IHC) assay.

6. The method according to claim 5, wherein: (a) at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% of the tumor cells have an IHC score of 1+ or 2+; (b) at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% of the tumor cells have an IHC score of 2+; (c) at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% of the tumor cells have an IHC score of 1+; (d) at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, or about 20% of the tumor cells have an IHC score of 1+, and wherein no more than about 1%, 2%, 3%, 4%, or 5% of the tumor cells have an IHC score of 2+ or 3+; and / or (e) at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, or about 20% of the tumor cells have an IHC score of 1+, and wherein no more than about 1%, 2%, 3%, 4%, or 5% of the tumor cells have an IHC score of 2+ or 3+.

7. The method according to claim 6, wherein: (a) no more than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, or about 20% of tumor cells have an IHC score of 2+, and no more than about 1% have an IHC score of 3+; (b) no tumor cells have an IHC score greater than 1+; or (c) No tumor cells had an IHC score greater than 2+.

8. The method of claim 6, further comprising the step of determining an H-score for the tumor, wherein the H-score is between about 10 and 300, between about 10 and about 250, between about 20 and about 225, between about 20 and about 200, between about 20 and about 175, or between about 20 and about 150.

9. The method of claim 8, wherein the H-score is no more than about 100, about 90, about 80, about 70, or about 50.

10. The method of claim 6, wherein the tumor is homogeneous or heterogeneous with respect to cMET expression and / or MET amplification.

11. The method of claim 10, wherein at least about 10%, 20%, or 30% of the tumor cells have a first frequently occurring IHC score selected from one of 0, 1+, 2+, and 3+, and at least about 10%, 20%, or 30% of the tumor cells have a second frequently occurring IHC score selected from one of 0, 1+, 2+, and 3+, wherein the first frequently occurring IHC score and the second frequently occurring IHC score are different.

12. The method of claim 11, wherein the first IHC score and the second IHC score are selected from the following score pairs: (0, +1), (0, +2), (0, +3), (+1, +2), (+1, +3), and (+2, +3).

13. The method of claim 12, wherein at least about 10%, 20%, or 30% of the tumor cells have a third frequently occurring IHC score, wherein the third score is different from the first frequently occurring IHC score and the second frequently occurring IHC score.

14. The method of claim 6, wherein the cancer has developed resistance to targeted therapy for one or more targetable mutations present in one or more genes selected from the group consisting of EGFR, ALK, KRAS, ROS, BRAF, NTRK1 / 2 / 3, MET, RET, ERBB2, and any other gene known to have a targetable mutation associated with the cancer.

15. The method of claim 14, wherein the targetable mutation is selected from one or more of the following: a) an EGFR gene mutation selected from the group consisting of an exon 20 T790M substitution, an exon 20 C797X substitution, an exon 21 L858R substitution, and an exon 19 deletion, optionally wherein the exon 19 deletion is an E746_A750 deletion as determined by a test approved by a regulatory agency; b) ALK gene rearrangement; c) a KRAS gene mutation, optionally wherein the mutation is an exon 1 G12C substitution; d) a BRAF gene mutation, optionally wherein the mutation is an exon 15 V600E substitution; e) a MET gene mutation, optionally wherein the mutation is an ex14 skipping mutation; f) ROS1 gene rearrangement, optionally wherein the ROS1 gene is fused to a gene or portion thereof selected from one of the following: CD74, EZR, SDC4, SLC34A2, CCCKC6, TFG, SLMAP, MYO5C, FIG, LIMA1, CLTC, GOPC, ZZCCHC8, CEP72, MLL3, KDELR2, LRIG3, MSN, MPRIP, WNK1, SLC6A17, TMEM106B, FAM135B, TPM3, and TDP52L1; g) a fusion of the NTRK1, 2 or 3 gene; and h) RET1 gene rearrangement, optionally wherein the rearrangement is a fusion with KIF5B or CCDC6.

16. The method of claim 6 or 15, wherein the cancer has amplification, mutation or overexpression of the ERBB2 gene, optionally wherein the ERBB2 gene has an insertion and / or nucleotide substitution in exon 20 encoding an amino acid substitution selected from one or more of: L755S, G776C, G660D, R678Q, E693K and Q709L.

17. The method of claim 6 or 15, wherein the anti-cMET ADC is administered as a monotherapy or adjunct to an additional anti-cancer agent, wherein the additional agent is administered according to a dosing regimen approved by its regulatory agency, optionally wherein the additional anti-cancer agent is an inhibitor and / or targeted agent of EGFR, ALK, KRAS, ROS, BRAF, NTRK1 / 2 / 3, MET, RET or ERBB2.

18. The method of claim 17, wherein the additional anticancer agent is selected from the group consisting of osimertinib (TAGRISSO®), afatinib (GIOTRIF®), axitinib (INLYTA®), bosutinib (BOSULIF®), crizotinib (XALKORI®), dasatinib (SPRYCE®), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (GLEEVEC®), lapatinib (I apatinib (TYVERB®), nilotinib (TASIGNA®), pazopanib (VOTRIENT®), ponatinib (ICLUSIG®), radotinib (SUPECT®), regorafenib (STIVARGA®), sorafenib (NEXAVAR®), sunitinib (SUTENT®), toceranib (PALLADIA®), and vatalanib; and / or wherein the additional anticancer agent is capable of inhibiting EGFR comprising an exon 21 L858R substitution or an exon 19 E746_A750 deletion.

19. The method of claim 17, wherein the ALK inhibitor is selected from the group consisting of alectinib, brigatinib, lorlatinib, ceritinib, and crizotinib; the KRAS inhibitor is selected from the group consisting of sotorasib and adagrasib; the BRAF inhibitor is selected from the group consisting of dabrafinib, vemurafenib, and trametinib; the MET inhibitor is selected from the group consisting of tepotinib, crizotinib, and kamastatinib. capmatinib; the ROS1 inhibitor is selected from entrectinib, crizotinib, ceritinib and lorlatinib; the NTRK1 / 2 / 3 inhibitor is selected from larotrectinib and entrectinib; the RET inhibitor is selected from selpercatinib, pralsetinib and cabozantinib; the ERBB2 targeted agent is selected from transtuzumab-deruxtecan and trastuzumab-emtansine.

20. The method of claim 17, wherein the additional anti-cancer agent comprises an inhibitor of PD1, optionally an anti-PD1 antibody, optionally wherein the anti-PD1 antibody is pembrolizumab (Keytruda), nivolumab (Opdivo), or cemiplimab (Letayo); or an inhibitor of PD-L1, optionally an anti-PD-L1 antibody, such as durvalumab or azetolizumab.

21. The method of claim 1, 6, or 15, wherein the cancer is resistant to prior treatment with an anti-cMET antibody, an anti-cMET ADC, chemotherapy, a small molecule directed against cMET, and / or radiation therapy.

22. The method of claim 1, 6, or 15, wherein the anti-cMET ADC is administered once every three weeks (Q3W) in an amount ranging from about 0.5 mg / kg to about 6.0 mg / kg, about 2.0 mg / kg to about 5.0 mg / kg, or about 4.5 mg / kg.

23. The method of claim 1, 6, or 15, wherein the anti-cMET ADC comprises an anti-cMET antibody connected to the drug component of the ADC via a linker.

24. The method of claim 23, wherein the anti-cMET antibody is a full-length antibody, optionally wherein the anti-cMET antibody is an IgG1 antibody.

25. The method of claim 24, wherein the anti-cMET antibody binds to cMET at physiological pH in vitro or in vivo with an affinity that is at least 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 30-fold, 100-fold, 300-fold, or 1000-fold greater than its affinity for cMET at pH 5.

4.

26. The method of claim 24, wherein the anti-cMET antibody comprises a VH chain comprising the amino acid sequence of SEQ ID NO: 236, SEQ ID NO: 237, and SEQ ID NO: 238, and a VL chain comprising the amino acid sequence of SEQ ID NO: 239, SEQ ID NO: 240, and SEQ ID NO:

241.

27. The method of claim 26, wherein the anti-cMET antibody comprises a VH chain comprising the amino acid sequence of SEQ ID NO: 15 and a VL chain comprising the amino acid sequence of SEQ ID NO:

16.

28. The method of claim 27, wherein the anti-cMET antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 75 and a light chain comprising the amino acid sequence of SEQ ID NO:

82.

29. The method of claim 28, wherein the linker is capable of being cleaved by a lysosomal enzyme, optionally wherein the enzyme is cathepsin B.

30. The method of claim 29, wherein the linker comprises a peptide selected from the group consisting of: Cit-Cit; Cit-Val; Val-Cit; Cit-Ala; Ala-Cit; Cit-Asn; Asn-Cit; Cit-Ser; Ser-Cit; Cit-Lys; Lys-Cit; Cit-Asp; Asp-Cit; Ala-Ala; Glu-Val; Val-Glu; Ala-Val; and Val-Ala; and salts thereof.

31. The method of claim 1, 6, 15, or 28, wherein the drug component of the ADC is a microtubule inhibitor, wherein the inhibitor is an auristatin.

32. The method of claim 31, wherein the ADC comprises a compound having the structure of formula (I): [DL-XY] n -Ab or a salt thereof, wherein each "D" represents a cytotoxic agent and / or cytostatic agent ("drug"); each "L" represents a linker; "Ab" represents a pH-dependent anti-cMET antigen-binding portion; each "XY" represents a functional group R on the linker x The "complementary" functional group R on the antigen binding portion y and n represents the number of drugs attached to the Ab of the ADC; optionally wherein the compound has the following structure (II): (II) And the anti-cMET antibody is Q397.

33. The method of claim 32, wherein the compound has the following structure (III): (III) or a pharmaceutically acceptable salt thereof, wherein n has an average value of 2 or is equal to 2, and the Ab is the full-length anti-cMET pH-antibody Q397.

34. The method of claim 1 , 6, 15, 28, or 33, wherein the human subject is a patient diagnosed with non-small cell lung cancer ("NSCLC") that overexpresses cMET, has a MET amplification, and / or a MET ex14 skipping mutation, the method comprising administering to the patient an effective amount of an anti-cMET antibody drug conjugate ("ADC") for a period of time sufficient to provide one or more therapeutic benefits, wherein the antibody component of the ADC exhibits cMET-specific pH-dependent binding, wherein the antibody comprises heavy and light chain CDRs present in the amino acid sequences set forth in one of the following pairs: SEQ ID NOs: 15 and 16; SEQ ID NOs: 5 and 6; SEQ ID NOs: 7 and 8; SEQ ID NOs: 9 and 10; SEQ ID NOs: 11 and 12; SEQ ID NOs: 13 and 14; SEQ ID NOs: 17 and 18; SEQ ID NOs: 19 and 20; SEQ ID NOs: 21 and 22; SEQ ID NOs: 23 and 24; SEQ ID NOs: 25 and 26; SEQ ID NOs: SEQ ID NOs: 27 and 28; SEQ ID NOs: 29 and 30; SEQ ID NOs: 31 and 32; and SEQ ID NOs: 33 and 34.

35. The method of claim 34, wherein the cancer is resistant to prior treatment with: (a) a microtubule inhibitor, optionally wherein the microtubule inhibitor is an auristatin; and / or (b) an anti-cMET ADC, an anti-cMET antibody, or a small molecule targeting cMET; and wherein the anti-cMET ADC is administered as a monotherapy or adjunctively with another anticancer agent, the other anticancer agent being administered according to a dosing regimen approved by its regulatory agency.

36. The method of claim 35, wherein the anti-cMET ADC is effective against non-squamous and / or squamous NSCLC; and / or wherein the NSCLC is wild-type for human EGFR, or wherein the NSCLC is mutated against human EGFR; Optionally wherein the NSCLC has been resistant to at least 1, 2, 3, 4, 5, 6, 7, 8 or more prior treatment regimens.

37. A pharmaceutical composition comprising MYTX-011 and a pharmaceutically acceptable carrier, optionally wherein the composition remains effective for treating cancer when frozen and re-thawed at least twice, optionally wherein the carrier comprises L-histidine; L-histidine HCl, monohydrate; D(+)-trehalose dihydrate; and polysorbate 80; Optionally wherein the composition is for use in treating NSCLC in a human subject or in a method of preparing a medicament for treating NSCLC in a human subject.

38. A method of treating a non-squamous non-small cell lung cancer ("nsNSCLC") tumor that expresses or overexpresses c-Met, the method comprising administering to a human subject having the NSCLC tumor an effective amount of the pharmaceutical composition of claim 41, wherein ≥ 25% of tumor cells in tumor tissue of the c-Met-expressing or overexpressing nsNSCLC from the subject have 2+ membrane or membrane plus cytoplasmic staining when assessed by c-Met immunohistochemistry (IHC).

39. The method of claim 1, 6, 15, 28, 33 or the use of claim 37, wherein the tumor comprises cells having FGFR3 amplification, a MET exon 14 mutation, or an EML4-ALK fusion; optionally wherein the subject has received at least 2 prior treatment regimens for the NSCLC, and / or wherein the subject's tumor is positive for a MET exon 14 mutation, optionally wherein the tumor has progressed following prior treatment with a tyrosine kinase inhibitor.

40. A pharmaceutical composition comprising a therapeutically effective amount of a pH-dependent, anti-cMET antibody drug conjugate (ADC), the ADC comprising two (2) heavy chains and two (2) light chains, each heavy chain having the sequence set forth in SEQ ID NO: 75, each light chain having the sequence set forth in SEQ ID NO: 82, wherein each light chain constant domain comprises the sequence set forth in SEQ ID NO: 158, wherein each light chain constant domain comprises a linker-drug conjugated thereto at a cysteine ​​(C) located at amino acid position 98 of SEQ ID NO: 158; optionally wherein each linker-drug comprises vcMMAE; optionally wherein the composition remains effective for treating cancer when frozen and re-thawed at least 2 times; and optionally wherein the composition further comprises L-histidine; L-histidine HCl, monohydrate; D(+)-trehalose dihydrate; and polysorbate 80.

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