COMBINATION THERAPY FOR CANCER TREATMENT
The present disclosure relates to methods for treating cancer, or preventing cancer recurrence or progression, comprising administering a patient an anti-CD38 antibody and a proteasome inhibitor.
1 . A method for treating cancer, or preventing cancer recurrence or progression in a patient in need thereof, the method comprising:
administering to the patient an anti-CD38 antibody and a proteasome inhibitor of formula (I)
or a pharmaceutically acceptable salt thereof, wherein ring A is selected from
and
Z 1 and Z 2 are each independently hydroxyl; or Z 1 and Z 2 together form a cyclic boronic ester having 2-20 carbon atoms, and optionally one or more heteroatoms selected from N, S, or O.
2 . The method of claim 1 , wherein the proteasome inhibitor of formula (I) is a compound of formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein: Z 1 and Z 2 are each independently hydroxyl; or Z 1 and Z 2 together form a cyclic boronic ester having 2-20 carbon atoms, and optionally one or more heteroatoms selected from N, S, or O.
3 . The method of claim 1 , wherein the proteasome inhibitor is a compound of formula (II)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are each independently —(CH 2 ) p —CO 2 H; wherein one of carboxylic acids optionally forms a further bond with the boron atom;
n is 0 or 1; and p is 0 or 1.
4 . The method of claim 1 , wherein the proteasome inhibitor is a compound of formula (III)
or a pharmaceutically acceptable salt thereof.
5 . The method of claim 1 , wherein the proteasome inhibitor is a compound of formula (IV)
its esters, or a pharmaceutically acceptable salt thereof.
6 . The method of claim 1 , wherein said anti-CD38 antibody is a human monoclonal antibody.
7 . The method of claim 6 , wherein said human monoclonal antibody is a human IgG1 monoclonal antibody.
8 . The method of claim 6 , wherein said anti-CD38 antibody is an antagonist of CD38.
9 . The method of claim 6 , wherein said anti-CD38 antibody is an isolated full-length antibody that binds to human CD38.
10 . The method of claim 9 , wherein said anti-CD38 antibody binds to CD38 having an amino acid sequence as set forth in SEQ ID NO: 15.
11 . The method of claim 6 , wherein said anti-CD38 antibody comprises:
a) a V L CDR1 region comprising the amino acid sequence as set forth in SEQ ID NO: 5;
b) a V L CDR2 region comprising the amino acid sequence as set forth in SEQ ID NO: 6;
c) a V L CDR3 region comprising the amino acid sequence as set forth in SEQ ID NO: 7;
d) a V H CDR1 region comprising the amino acid sequence as set forth in SEQ ID NO: 10;
e) a V H CDR2 region comprising the amino acid sequence as set forth in SEQ ID NO: 11; and
f) a V H CDR3 region comprising the amino acid sequence as set forth in SEQ ID NO: 12.
12 . The method of claim 6 , wherein said anti-CD38 antibody comprises a V L region having the amino acid sequence as set forth in SEQ ID NO: 4.
13 . The method of claim 6 , wherein said anti-CD38 antibody comprises a V H region having the amino acid sequence as set forth in SEQ ID NO: 9.
14 . The method of claim 6 , wherein said anti-CD38 antibody comprises a V L region having the amino acid sequence as set forth in SEQ ID NO: 4 and a V H region having the amino acid sequence as set forth in SEQ ID NO: 9.
15 . The method of claim 1 , wherein said proteasome inhibitor is a compound of formula (IIIa) and said anti-CD38 antibody comprises a V L region having the amino acid sequence as set forth in SEQ ID NO: 4 and a V H region having the amino acid sequence as set forth in SEQ ID NO: 9.
16 . The method of claim 1 , wherein said proteasome inhibitor is a compound of formula (IIa) and said anti-CD38 antibody comprises:
a) a V L CDR1 region comprising the amino acid sequence as set forth in SEQ ID NO: 5;
b) a V L CDR2 region comprising the amino acid sequence as set forth in SEQ ID NO: 6;
c) a V L CDR3 region comprising the amino acid sequence as set forth in SEQ ID NO: 7;
d) a V H CDR1 region comprising the amino acid sequence as set forth in SEQ ID NO: 10;
e) a V H CDR2 region comprising the amino acid sequence as set forth in SEQ ID NO: 11; and
f) a V H CDR3 region comprising the amino acid sequence as set forth in SEQ ID NO: 12.
17 . The method of claim 1 , wherein the cancer is multiple myeloma, lymphoma, refractory multiple myeloma or lymphoma, or recurrence of multiple myeloma or lymphoma.
18 . The method of claim 1 , wherein the proteasome inhibitor is administered with one or more therapeutic agents.
19 . The method of claim 18 , wherein the therapeutic agent is melphalan, lenalidomide, cyclophosphamide, or dexamethasone.
20 . A therapeutic combination comprising a compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt thereof, and an anti-CD38 antibody.
21 . A pharmaceutical combination comprising a composition comprising a compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt thereof, and a composition comprising an anti-CD38 antibody.