ANTI-DLL3 ANTIBODY DRUG CONJUGATES AND METHODS OF USE
Provided are novel anti-DLL3 antibodies and antibody drug conjugates, and methods of using such anti-DLL3 antibodies and antibody drug conjugates to treat cancer.
1 . A method of treating a subject having a tumor exhibiting a DLL3 H-score of at least 90 on a 300 point scale and/or ≥10% positively stained DLL3 cells comprising the step of administering a DLL3 ADC.
2 . The method of claim 1 wherein the DLL3 ADC comprises cytotoxin selected from the group consisting of PBDs, calicheamicins, auristatins, maytansinoids and duocarmycins.
3 . The method of claim 2 wherein the cytotoxin comprises a PBD.
4 . The method of claim 3 wherein the PBD comprises PBD1.
5 . The method of any one of claims 1 - 4 comprising a DLL3 ADC that binds to a tumor initiating cell expressing DLL3.
6 . The method of any one of claims 1 - 5 wherein the DLL3 ADC comprises an antibody which is a chimeric, CDR grafted, human or humanized antibody, or a fragment thereof.
7 . The method of claim 6 wherein the antibody is an internalizing antibody.
8 . The method of any one of claims 1 - 7 wherein the tumor exhibits a DLL3 H-score of at least 120 on a 300 point scale.
9 . The method of any one of claims 1 - 8 wherein the tumor exhibits a DLL3 H-score of at least 180 on a 300 point scale.
10 . The method of any one of claims 1 - 9 wherein the tumor comprises a neuroendocrine tumor.
11 . The method of any one of claims 1 - 10 wherein the tumor comprises a small cell lung cancer (SCLC) tumor.
12 . The method of any one of claims 1 - 10 wherein the tumor comprises a large cell neuroendocrine cancer (LCNEC) tumor.
13 . The method of any one of claims 1 - 12 wherein the tumor comprises a medullary thyroid cancer tumor.
14 . The method of any one of claims 1 - 13 wherein the subject is treated with a DLL3 ADC regimen comprising a 0.2 mg/kg Q3W×3 dosing regimen.
15 . The method of any one of claims 1 - 13 wherein the subject is treated with a DLL3 ADC regimen comprising a 0.3 mg/kg Q6W×2 dosing regimen.
16 . The method of claim 14 or 15 wherein the subject is treated at progression following the DLL3 ADC regimen.
17 . The method of claim 14 or 15 wherein the subject is shifted to a DLL3 ADC maintenance therapy following the DLL3 ADC regimen.
18 . The method of any one of claims 1 - 17 wherein the subject is a front line patient.
19 . The method of any one of claims 1 - 17 wherein the subject is a second line patient.
20 . The method of any one of claims 1 - 17 wherein the subject is a third line patient.
21 . The method of any one of claims 1 - 20 wherein the DLL3 ADC comprises SC16LD.5.
22 . The method of any one of claims 1 - 20 wherein the DLL3 ADC comprises hSC16.56ss1DL6.
23 . A method of treating a subject having a tumor comprising the steps of:
obtaining a sample of the tumor;
interrogating the tumor sample to calculate a DLL3 H-score and/or determine the percentage of positively stained DLL3 cells
treating the patient with a DLL3 ADC when the calculated DLL3 H-score is at least 90 on a 300 point scale and/or the positively stained DLL3 cells comprise ≥10% of the tumor cells.
24 . The method of claim 23 wherein the interrogation step comprises immunohistochemistry.
25 . A lyophilized composition comprising the antibody drug conjugate (ADC) of the formula Ab-[L-D]n or a pharmaceutically acceptable salt thereof wherein:
Ab comprises an anti-DLL3 antibody;
L comprises an optional linker;
D comprises a drug; and
n is an integer from 1 to 20.
26 . The lyophilized composition of claim 25 wherein D comprises a PBD.
27 . The lyophilized composition of claim 25 further comprising a pharmaceutically acceptable sugar.
28 . The lyophilized composition of claim 26 wherein the ADC comprises SC16LD6.5.
29 . The lyophilized composition of claim 26 wherein the ADC comprises hSC16.56ss1DL6.
30 . An article of manufacture useful for diagnosing or treating DLL3 associated disorders comprising the composition of claim 25 .
31 . A method for treating cancer comprising the steps of:
reconstituting the lyophilized composition of claim 25 to provide a liquid pharmaceutical composition; and
administering the liquid pharmaceutical composition to a subject in need thereof.
32 . The method of claim 31 wherein the cancer comprises a tumor exhibiting neuroendocrine features.
33 . The method of claim 32 , wherein the cancer comprises a neuroendocrine tumor
34 . The method of claim 30 wherein the cancer comprises small cell lung cancer.
35 . The method of claim 30 wherein the cancer comprises large cell neuroendocrine cancer.
36 . An article of manufacture useful for diagnosing or treating DLL3 associated disorders comprising a receptacle comprising a lyophilized DLL3 ADC and associated with instructional materials for using said article of manufacture to treat or diagnose the DLL3 associated disorder.
37 . The article of manufacture of claim 36 wherein said DLL3 ADC comprises a PBD.
38 . A method of treating a subject having a tumor comprising the step of administering a DLL3 ADC having a terminal half-life of greater than about six days.
39 . The method of claim 38 wherein said DLL3 ADC has a terminal half-life of greater than about seven days.
40 . The method of claim 38 wherein said DLL3 ADC has a terminal half-life of greater than about eight days.
41 . The method of claim 38 wherein said DLL3 ADC has a terminal half-life of greater than about nine days.
42 . The method of claim 38 wherein said DLL3 ADC has a terminal half-life of greater than about 10 days.
43 . The method of any one of claims 38 - 42 wherein the DLL3 ADC comprises cytotoxin selected from the group consisting of PBDs, calicheamicins, auristatins, maytansinoids and duocarmycins.
44 . The method of claim 43 wherein the cytotoxin comprises a PBD.
45 . The method of claim 44 wherein the PBD comprises PBD1.
46 . The method of any one of claims 38 - 45 wherein the DLL3 ADC comprises an antibody which is a chimeric, CDR grafted, human or humanized antibody, or a fragment thereof.
47 . The method of claim 46 wherein the antibody is an internalizing antibody.
48 . The method of any one of claims 38 - 45 wherein the tumor comprises a tumor exhibiting neuroendocrine features.
49 . The method of claim 46 wherein the tumor comprises a neuroendocrine tumor.
50 . The method of any one of claims 38 - 47 wherein the tumor comprises a small cell lung cancer (SCLC) tumor.
51 . The method of any one of claims 38 - 47 wherein the tumor comprises a large cell neuroendocrine cancer (LCNEC) tumor.
52 . The method of any one of claims 38 - 51 wherein the subject is treated with a DLL3 ADC regimen comprising a 0.2 mg/kg Q3W dosing regimen.
53 . The method of claim 52 wherein the subject is treated with a DLL3 ADC regimen comprising a 0.2 mg/kg Q3W×3 dosing regimen.
54 . The method of any one of claims 38 - 51 wherein the subject is treated with a DLL3 ADC regimen comprising a 0.3 mg/kg Q6W dosing regimen.
55 . The method of claim 54 wherein the subject is treated with a DLL3 ADC regimen comprising a 0.3 mg/kg Q6W×2 dosing regimen.
56 . The method of claims 52 to 55 wherein the subject is treated at progression following the DLL3 ADC regimen.
57 . The method of claims 52 to 55 wherein the subject is shifted to a DLL3 ADC maintenance therapy following the DLL3 ADC regimen.
58 . The method of any one of claims 38 - 57 wherein the subject is a front line patient.
59 . The method of any one of claims 38 - 57 wherein the subject is a second line patient.
60 . The method of any one of claims 38 - 57 wherein the subject is a third line patient.
61 . The method of any one of claims 38 - 60 wherein the DLL3 ADC comprises SC16LD.5.
62 . The method of any one of claims 38 - 60 wherein the DLL3 ADC comprises hSC16.56ss1DL6.
63 . A method of reducing the frequency of cancer stem cells in a subject in need thereof comprising the step of administering a DLL3 ADC having a terminal half-life of greater than about six days.
64 . A DLL3 ADC comprising the following formula:
wherein Ab comprises an anti-DLL3 antibody or immunoreactive fragment thereof.
65 . The DLL3 ADC of claim 64 wherein the anti-DLL3 antibody comprises a site-specific antibody.
66 . The DLL3 ADC of claim 64 wherein the anti-DLL3 antibody is hSC16.56ss1.
67 . A method of reducing the frequency of cancer stem cells in a subject in need thereof comprising the steps of administering a DLL3 ADC and an anti-PD-1 antibody.
68 . The method of claim 67 wherein the DLL3 ADC comprises SC16LD5
69 . The method of claim 67 wherein the DLL3 ADC comprises hSC16.56551DL6.
70 . A method of reducing the frequency of cancer stem cells in a subject in need thereof comprising the steps of administering a DLL3 ADC and an anti-PD-L1 antibody.
71 . The method of claim 70 wherein the DLL3 ADC comprises SC16LD5
72 . The method of claim 70 wherein the DLL3 ADC comprises hSC16.56ss1DL6.
73 . A method of treating cancer in a subject in need thereof comprising the steps of administering a DLL3 ADC and an anti-PD-1 antibody.
74 . The method of claim 73 wherein the DLL3 ADC comprises SC16LD5
75 . The method of claim 73 wherein the DLL3 ADC comprises hSC16.56ss1DL6.
76 . A method of treating cancer in a subject in need thereof comprising the steps of administering a DLL3 ADC and an anti-PD-L1 antibody.
77 . The method of claim 76 wherein the DLL3 ADC comprises SC16LD5
78 . The method of claim 76 wherein the DLL3 ADC comprises hSC16.56ss1DL6.