US2017348429A1PendingUtilityA1
ANTI-cMET ANTIBODY DRUG CONJUGATES AND METHODS FOR THEIR USE
Est. expiryMay 17, 2036(~9.8 yrs left)· nominal 20-yr term from priority
A61P 35/00A61K 45/06A61K 47/6849A61K 31/517A61K 47/6811A61K 47/6803A61K 2300/00A61K 47/68035A61K 47/68031A61K 47/6871A61K 45/00C07K 16/2863A61K 47/6857A61K 47/6851A61K 47/68
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Claims
Abstract
The present disclosure provides antibody drug conjugates that bind human cMET, their methods of making, and their uses to treat patients having cancer.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A method of treating a solid tumor cancer that overexpresses cMet, comprising administering to a human subject having said cancer an anti-cMet antibody drug conjugate (“ADC”) in an amount and for a period of time sufficient to provide a therapeutic benefit.
2 . The method of claim 1 in which the cMet overexpressing cancer is of a cancer type wherein cMet is overexpressed in at least about 10% of a patient population having the cancer type.
3 . The method of claim 1 in which a biopsy of the cMet overexpressing tumor tissue from the subject has an IHC score of 2+ and/or an H-score from 150 to 224, when measured according to the cMet ABBV-ADC staining protocol.
4 . The method of claim 1 in which a biopsy of the cMet overexpressing tumor tissue from the subject has an IHC score of 3+ and/or an H-score greater than 225, when measured according to the cMet ABBV-ADC staining protocol.
5 . The method according to any one of claims 1 - 4 in which the cMet overexpressing cancer is non-small cell lung cancer (“NSCLC”).
6 . The method of claim 5 , in which the NSCLC is a non-squamous NSCLC.
7 . The method of claim 5 in which the NSCLC is squamous NSCLC.
8 . The method of claim 6 in which the non-squamous NSCLC is an adeonocarcinoma.
9 . The method of claim 1 in which the cancer is colorectal cancer (“CRC”).
10 . The method of claim 1 in which the cancer is head & neck (“H&N”) cancer.
11 . The method of claim 1 in which the cancer is pancreatic cancer.
12 . The method of claim 1 in which the cMet overexpressing cancer is resistant to prior treatment with targeted and/or non-targeted chemotherapy.
13 . The method of claim 1 in which the cMet overexpressing cancer is resistant to prior treatment with an anti-cMet antibody.
14 . The method of claim 1 in which the anti-cMet ADC is administered as monotherapy.
15 . The method of claim 1 in which the anti-cMet ADC is administered adjunctive to an additional anticancer agent, where the additional agent is administered according to its FDA-approved dosing regimen.
16 . The method of claim 15 in which the additional anticancer agent is an inhibitor of epidermal growth factor receptor (“EGFR”).
17 . The method of claim 16 in which the additional anticancer agent is erlotinib.
18 . The method of claim 15 in which the additional anticancer agent is an inhibitor of PD1.
19 . The method of claim 18 in which the inhibitor of PD1 is an anti-PD1 antibody.
20 . The method of claim 19 in which the anti-PD1 antibody is nivolumab.
21 . The method of any one of claims 1 - 20 in which the anti-cMet ADC is administered in an amount ranging from about 0.15 mg/kg to about 3.3 mg/kg once every three weeks.
22 . The method of claim 21 in which the anti-cMet ADC is administered in an amount of about 2.7 mg/kg.
23 . The method of any one of claims 1 - 20 in which the anti-cMet ADC is administered in an amount ranging from about 0.15 mg/kg to about 3.3 mg/kg once every two weeks.
24 . The method of claim 23 in which the anti-cMet ADC is administered in an amount of about 1.6 mg/kg once every two weeks.
25 . The method of claim 23 in which the anti-cMet ADC is administered in an amount of about 1.9 mg/kg once every two weeks.
26 . The method of any one of claims 1 - 25 in which the anti-cMet ADC comprises an anti-cMet antibody linked to a cytostatic and/or cytotoxic agent by way of a linker.
27 . The method of claim 26 in which the anti-cMet antibody is a full-length antibody.
28 . The method of claim 26 in which the anti-cMet antibody comprises a V H chain comprising three CDRs, namely V H CDR #1 (SEQ ID NO:112), V H CDR #2 (SEQ ID NO:113) and V H CDR #3 (SEQ ID NO: 114); a V L chain comprising three CDRs, namely V L CDR #1 (SEQ ID NO: 115), V L CDR #2 (SEQ ID NO: 116) and V L CDR #3 (SEQ ID NO: 117); and a modified hinge region of SEQ ID NO: 170.
29 . The method of claim 26 in which the anti-cMet antibody comprises a V H chain of SEQ ID NO: 78; a V L chain of SEQ ID NO: 79; and a modified hinge region of SEQ ID NO: 170.
30 . The method of claim 29 in which the anti-cMet antibody is an IgG1.
31 . The method of claim 26 in which the anti-cMet antibody comprises a heavy chain of SEQ ID NO: 86 and a light chain of SEQ ID NO: 87.
32 . The method of claim 31 in which the anti-cMet antibody is ABBV399.
33 . The method of claim 26 in which the anti-cMet antibody comprises a heavy chain of SEQ ID NO: 171 and a light chain of SEQ ID NO: 172.
34 . The method of claim 33 in which the anti-cMet antibody is ABT-700 (S238C)-PBD.
35 . The method of claim 26 in which the anti-cMet antibody comprises the six CDRs of the antibody STI-D0602/STI-0602.
36 . The method of claim 26 in which the anti-cMet antibody comprises a V H chain of STI-D0602/STI-0602 and a V L chain of STI-D0602/STI-0602.
37 . The method of claim 26 in which the linker comprises a segment according to one or more of structural formulae (IVa), (IVb), (IVc) and (IVd):
or a salt thereof, in which:
peptide represents a peptide (illustrated C→N and not showing the carboxy and amino “termini”) cleavable by Cathepsin B;
T represents a polymer comprising one or more ethylene glycol units or an alkylene chain, or combinations thereof;
R a is selected from hydrogen, alkyl, sulfonate and methyl sulfonate;
p is an integer ranging from 0 to 5;
q is 0 or 1;
x is 0 or 1;
y is 0 or 1;
represents the point of attachment of the linker to the cytotoxic and/or cytostatic agent; and
* represents the point of attachment to the remainder of the linker.
38 . The method of claim 37 in which peptide is selected from the group consisting of Val-Cit; Cit-Val; Ala-Ala; Ala-Cit; Cit-Ala; Asn-Cit; Cit-Asn; Cit-Cit; Val-Glu; Glu-Val; Ser-Cit; Cit-Ser; Lys-Cit; Cit-Lys; Asp-Cit; Cit-Asp; Ala-Val; and Val-Ala and salts thereof.
39 . The method of claim 38 in which the peptide is Val-Cit.
40 . The method of claim 26 in which the anti-cMet ADC has an average drug-to-antibody ratio (“DAR”) in the range of 0-10.
41 . The method of claim 26 in which the anti-cMet ADC has an average drug-to-antibody ratio (“DAR”) in the range of 1-4.
42 . The method of claim 41 in which the anti-cMet ADC has a DAR in the range of 2-4.
43 . The method of claim 41 in which the anti-cMet ADC has a DAR of about 3.1.
44 . The method of claim 41 in which the anti-cMet ADC has an about 1:1 ratio of E2 and E4 ADC.
45 . The method of claim 41 in which the anti-cMet ADC has a DAR of 3.0.
46 . The method of claim 26 in which the cytostatic and/or cytotoxic agent is a microtubule inhibitor.
47 . The method of claim 46 in which the microtubule inhibitor is an auristatin.
48 . The method of claim 47 in which the auristatin is MMAE or MMAF.
49 . The method of claim 47 in which the auristatin is MMAE.
50 . The method of claim 26 in which the anti-cMet ADC is a compound according to structural formula (I):
[D-L-XY-] n -Ab (I)
or a salt thereof, in which:
D is the cytotoxic and/or cytostatic agent;
L is the linker;
Ab is the anti-cMet antibody;
XY represents a covalent linkage linking linker L to antibody Ab; and
n has a value ranging from 2 to 8.
51 . The method of claim 50 in which n has a value of 2, 3 or 4.
52 . The method of claim 50 in which XY is a linkage formed with an amino group on anti-cMet antibody Ab.
53 . The method of claim 50 in which XY is an amide or a thiourea.
54 . The method of claim 50 in which XY is a linkage formed with a sulfhydryl group on anti-cMet antibody Ab.
55 . The method of claim 50 in which XY is a thioether.
56 . The method of claim 50 in which the compound according to structural formula (I) has the structure of formula (IIa):
57 . The method of claim 56 in which anti-cMet antibody is ABT-700.
58 . The method of claim 50 in which the compound of structural formula (I) has the following structure:
59 . The method of claim 58 in which anti-cMet antibody is ABT-700.
60 . The method of claim 50 in which the compound according to structural formula (I) has the structure of formula (IIb):
61 . The method of claim 60 in which anti-cMet antibody is ABT-700.
62 . The method of claim 50 in which the compound according to structural formula (I) has the following structure:
63 . The method of claim 62 in which anti-cMet antibody b is ABT-700.
64 . A method of treating a human patient diagnosed with non-small cell lung cancer (“NSCLC”) comprising administering to the patient an anti-cMet antibody drug conjugate (“ADC”) in an amount and for a period of time sufficient to provide therapeutic benefit.
65 . The method of claim 64 in which the NSCLC tumor tissue has an immunohistochemistry (“IHC”) H-score of greater than or equal to 150 when measured according to the cMet ABBV-ADC staining protocol or an IHC score of 2+.
66 . The method of claim 64 in which the NSCLC tumor tissue has an immunohistochemistry (“IHC”) H-score of greater than 225 when measured according to the cMet ABBV-ADC staining protocol or an IHC score of 3+.
67 . The method of claim 64 in which the NSCLC tumor tissue has an IHC score of 2+ and/or an H-score from 150 to 224, when measured according to the cMet ABBV-ADC staining protocol.
68 . The method according to any one of claims 64 , 65 , and 66 in which the NSCLC is a non-squamous cell carcinoma.
69 . The method according to any one of of claims 64 , 65 , and 67 in which the NSCLC is a squamous cell carcinoma.
70 . The method according to claim 64 in which the anti-cMet ADC is administered as monotherapy.
71 . The method according to claim 64 in which the anti-cMet ADC is administered adjunctive to an additional anticancer agent, where the additional agent is administered according to its FDA-approved dosing regimen.
72 . The method of claim 71 in which the additional anticancer agent is an inhibitor of epidermal growth factor receptor (“EGFR”).
73 . The method of claim 72 in which the additional anticancer agent is erlotinib, administered once daily.
74 . The method of claim 71 in which the additional anticancer agent is an inhibitor of PD1.
75 . The method of claim 74 in which the inhibitor of PD1 is an anti-PD1 antibody.
76 . The method of claim 75 in which the anti-PD1 antibody is nivolumab.
77 . The method of claim 64 in which the anti-cMet ADC is administered in an amount ranging from about 0.15 mg/kg to about 3.3 mg/kg, once every 3 weeks.
78 . The method of claim 77 in which the anti-cMet ADC is administered in an amount of about 2.7 mg/kg once every 3 weeks.
79 . The method of claim 64 in which the anti-cMet ADC is administered in an amount ranging from about 0.15 mg/kg to about 3.3 mg/kg, once every 2 weeks.
80 . The method of claim 79 in which the anti-cMet ADC is administered in an amount of about 1.6 mg/kg, once every 2 weeks.
81 . The method of claim 64 in which the anti-cMet ADC is administered in an amount of about 1.9 mg/kg, once every 2 weeks.
82 . The method of any one of claims 64 through 81 in which the anti-cMet ADC comprises an anti-cMet antibody linked to a cytostatic and/or cytotoxic agent by way of a linker.
83 . The method of claim 82 in which the anti-cMet antibody is a full-length antibody.
84 . The method of claim 82 in which the anti-cMet antibody comprises a V H chain comprising three CDRs, namely V H CDR #1 (SEQ ID NO:112), V H CDR #2 (SEQ ID NO:113) and V H CDR #3 (SEQ ID NO: 114); a V L chain comprising three CDRs, namely V L CDR #1 (SEQ ID NO: 115), V L CDR #2 (SEQ ID NO: 116) and V L CDR #3 (SEQ ID NO: 117); and a modified hinge region of SEQ ID NO: 170.
85 . The method of claim 84 in which the anti-cMet antibody comprises a V H chain of SEQ ID NO: 78; a V L chain of SEQ ID NO: 79; and a modified hinge region of SEQ ID NO: 170.
86 . The method of claim 85 in which the anti-cMet antibody is an IgG1.
87 . The method of claim 84 in which the anti-cMet antibody comprises a heavy chain of SEQ ID NO: 86 and a light chain of SEQ ID NO: 87.
88 . The method of claim 84 in which the anti-cMet antibody comprises a heavy chain of SEQ ID NO: 171 and a light chain of SEQ ID NO: 172.
89 . The method of claim 82 in which the anti-cMet antibody comprises comprises the six CDRs of the antibody STI-D0602/STI-0602.
90 . The method of claim 89 in which the anti-cMet antibody is an IgG1.
91 . The method of claim 82 in which the anti-cMet antibody comprises a V H chain of STI-D0602/STI-0602 and a V L chain of STI-D0602/STI-0602.
92 . The method of claim 91 in which the anti-cMet antibody is an IgG1.
93 . The method of claim 82 in which the linker is cleavable by a lysosomal enzyme.
94 . The method of claim 93 in which the lysosomal enzyme is Cathepsin B.
95 . The method of claim 94 in which the linker comprises a segment according to one or more of structural formulae (IVa), (IVb), (IVc) and (IVd):
or a salt thereof, in which:
peptide represents a peptide (illustrated C→N and not showing the carboxy and amino “termini”) cleavable by Cathepsin B;
T represents a polymer comprising one or more ethylene glycol units or an alkylene chain, or combinations thereof;
R a is selected from hydrogen, alkyl, sulfonate and methyl sulfonate;
p is an integer ranging from 0 to 5;
q is 0 or 1;
x is 0 or 1;
y is 0 or 1;
represents the point of attachment of the linker to the cytotoxic and/or cytostatic agent; and
* represents the point of attachment to the remainder of the linker.
96 . The method of claim 95 in which peptide is selected from the group consisting of Val-Cit; Cit-Val; Ala-Ala; Ala-Cit; Cit-Ala; Asn-Cit; Cit-Asn; Cit-Cit; Val-Glu; Glu-Val; Ser-Cit; Cit-Ser; Lys-Cit; Cit-Lys; Asp-Cit; Cit-Asp; Ala-Val; and Val-Ala and salts thereof.
97 . The method of claim 96 in which the peptide is Val-Cit.
98 . The method of claim 82 in which the anti-cMet ADC has an average drug-to-antibody ratio (“DAR”) in the range of 0-10.
99 . The method of claim 82 in which the anti-cMet ADC has an average drug-to-antibody ratio (“DAR”) in the range of 1-4.
100 . The method of claim 99 in which the anti-cMet ADC has a DAR in the range of 2-4.
101 . The method of claim 99 in which the anti-cMet ADC has a DAR of about 3.1.
102 . The method of claim 99 in which the anti-cMet ADC has an about 1:1 ratio of E2 and E4 ADC.
103 . The method of claim 99 in which the anti-cMet ADC has a DAR of 3.0.
104 . The method according to any one of claims 82 through 103 in which the cytostatic and/or cytotoxic agent is a microtubule inhibitor.
105 . The method of claim 104 in which the microtubule inhibitor is an auristatin.
106 . The method of claim 105 in which the auristatin is MMAE or MMAF.
107 . The method of claim 106 in which the auristatin is MMAE.
108 . The method according to claim 82 in which the anti-cMet ADC is a compound according to structural formula (I):
[D-L-XY-] n -Ab (I)
or a salt thereof, in which:
D is the cytotoxic and/or cytostatic agent;
L is the linker;
Ab is the anti-cMet antibody;
XY represents a covalent linkage linking linker L to antibody Ab; and
n has a value ranging from 2 to 8.
109 . The method of claim 108 in which n has a value of 2, 3 or 4.
110 . The method of claim 108 in which XY is a linkage formed with an amino group on anti-cMet antibody Ab.
111 . The method of claim 108 in which XY is an amide or a thiourea.
112 . The method of claim 108 in which XY is a linkage formed with a sulfhydryl group on anti-cMet antibody Ab.
113 . The method of claim 108 in which XY is a thioether.
114 . The method of claim 108 in which the compound according to structural formula (I) has the structure of formula (IIa):
115 . The method of claim 114 in which anti-cMet antibody is ABT-700.
116 . The method of claim 108 in which the compound of structural formula (I) has the following structure:
117 . The method of claim 116 in which anti-cMet antibody is ABT-700.
118 . The method of claim 108 in which the compound according to structural formula (I) has the structure of formula (IIb):
119 . The method of claim 118 in which anti-cMet antibody is ABT-700.
120 . The method of claim 108 in which the compound according to structural formula (I) has the following structure:
121 . The method of claim 120 in which anti-cMet antibody is ABT-700.
122 . A method of treating a human subject having a NSCLC tumor with an IHC score of at least 2+ or an H score of 150 or greater in at least one tumor biopsy from the subject, comprising administering to the subject an anti-cMet ADC in an amount of about 2.7 mg/kg once every two weeks or once every 3 weeks, in which the anti-cMet ADC is a compound according to the following structure:
or a pharmaceutically acceptable salt thereof, in which n has a value ranging from 2-4 and Ab is a full-length anti-cMet antibody.
123 . The method of claim 122 in which the anti-cMet antibody is ABT-700.
124 . The method of claim 123 in which the anti-cMet ADC is administered as monotherapy.
125 . The method of claim 122 in which the anti-cMetADC is administered adjunctive to an additional anticancer agent.
126 . The method of claim 125 in which the additional anticancer agent is erlotinib.
127 . The method of claim 125 in which the additional anticancer agent is Nivolumab.
128 . The method of claim 50 in which the drug is a pyrrolobenzodiazepine (PBD), preferably PBD ((S)-2-(4-aminophenyl)-7-methoxy-8-(3-(((S)-7-methoxy-2-(4-methoxyphenyl)-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)propoxy)-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(11aH)-one); SG2000 (SJG-136; (11aS,11a′S)-8,8′-(propane-1,3-diylbis(oxy))bis(7-methoxy-2-methylene-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(11aH)-one)) (or SGD-1882).
129 . The method of claim 128 in which the drug is a pyrrolobenzodiazepine (PBD), preferably SGD-1882.
130 . The method according to claim 50 , in which the compound of formula I has the following structure:
in which Ab is the antibody and n is 2.
131 . The method according to claim 130 in which the antibody comprises an heavy chain of SEQ ID NO: 171 and a light chain of SEQ ID NO:172.
132 . The method according to claim 50 in which the cMet ADC is the compound of formula
in which the antibody comprises an heavy chain of SEQ ID NO: 171 and a light chain of SEQ ID NO:172.
133 . A method of treating a human subject having a NSCLC adenocarcinoma, comprising administering to the subject ABBV-399 once every 3 weeks in an amount of about 2.7 mg/kg, in which the adenocarcinoma has an H-score of at least 225.
134 . A method of treating a human subject having a NSCLC adenocarcinoma, comprising administering to the subject ABBV-399 once every 3 weeks in an amount of about 2.7 mg/kg, in which the adenocarcinoma has an IHC score of 3+.
135 . The method according to any one of claims 133 and 134 , in which ABBV-399 is administered adjunctive to erlotinib, in which the the erlotinib is administered once daily at 150 mg.
136 . A method of treating a human subject having a NSCLC squamous cell carcinoma, comprising administering to the subject ABBV-399 once every 2 weeks in an amount of about 1.6 mg/kg or 1.9 mg/kg, in which the squamous cell carcinoma has an H-score of from 150 to 224.
137 . A method of treating a human subject having a NSCLC squamous cell carcinoma, comprising administering to the subject ABBV-399 once every 2 weeks in an amount of about 1.6 or 1.9 mg/kg, in which the squamous cell carcinoma has an IHC score of 2+.Cited by (0)
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