HER3 radioimmunotherapy for the treatment of solid cancers
Provided are compositions and methods for treating a solid cancer such as a HER3-positive tumor in a subject by administering an effective amount of a HER3-targeting agent labeled with a radionuclide such as 225 Ac, 177 Lu, 131 I, 90 Y, 213 Bi, 211 At, 213 Bi, 227 Th, or 212 Pb, alone or in combination with other therapeutic agents or modalities. The effective amount of the radiolabeled HER3-targeting agent may be a maximum tolerate dose administered in a single bolus or in fractionated doses that together equal the maximum tolerated dose.
1 . A method for treating a solid cancer comprising HER3-positive cancer cells in a mammalian subject, the method comprising:
administering to a mammalian subject afflicted with a solid cancer comprising HER3-positive cancer cells a therapeutically effective amount of a radionuclide labeled HER3 targeting antibody comprising:
radionuclide labeled barecetamab; radionuclide labeled patritumab; radionuclide labeled seribantumab; radionuclide labeled lumretuzumab; radionuclide labeled elgemtumab;
a radionuclide labeled antibody comprising an immunoglobulin heavy chain variable region comprising a CDR-H1 comprising SEQ ID NO:15, a CDR-H2 comprising SEQ ID NO:16, and a CDR-H3 comprising SEQ ID NO:17, and an immunoglobulin light chain variable region comprising a CDR-L1 comprising SEQ ID NO:18, a CDR-L2 comprising SEQ ID NO:19, and a CDR-L3 comprising SEQ ID NO:20;
a radionuclide labeled antibody comprising an immunoglobulin heavy chain variable region comprising SEQ ID NO:21 and an immunoglobulin light chain variable region comprising SEQ ID NO:22; or
a radionuclide labeled antibody comprising an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:23 and an immunoglobulin light chain amino acid sequence of SEQ ID NO: 24.
2 . The method of claim 1 , wherein the radionuclide labeled HER3 targeting antibody comprises 225 Ac as a radionuclide label.
3 . The method of claim 1 , wherein the radionuclide labeled HER3 targeting antibody comprises a humanized antibody against HER3.
4 . The method of claim 1 , wherein the radionuclide labeled HER3 targeting antibody comprises one or more of barecetamab, patritumab, seribantumab, lumretuzumab, and elgemtumab.
5 . The method of claim 1 , wherein the radionuclide labeled HER3 targeting antibody comprises a monoclonal antibody comprising:
(i) an immunoglobulin heavy chain variable region comprising a CDR-H1 comprising SEQ ID NO:15, a CDR-H2 comprising SEQ ID NO: 16, and/or a CDR-H3 comprising SEQ ID NO:17, and an immunoglobulin light chain variable region comprising a CDR-L1 comprising SEQ ID NO:18, a CDR-L2 comprising SEQ ID NO:19, and/or a CDR-L3 comprising SEQ ID NO:20;
(ii) an immunoglobulin heavy chain variable region comprising SEQ ID NO:21 and an immunoglobulin light chain variable region comprising SEQ ID NO: 22; or
(iii) an immunoglobulin heavy chain amino acid sequence of SEQ ID NO: 23 and an immunoglobulin light chain amino acid sequence of SEQ ID NO:24.
6 . The method of claim 1 , wherein the solid cancer is a breast cancer, gastric cancer, bladder cancer, cervical cancer, endometrial cancer, skin cancer, stomach cancer, testicular cancer, esophageal cancer, bronchioloalveolar cancer, prostate cancer, colorectal cancer, ovarian cancer, cervical epidermoid cancer, pancreatic cancer, lung cancer, renal cancer, head and neck cancer, or any combination thereof.
7 . The method of claim 1 , wherein the solid cancer is ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, or any combination thereof.
8 . The method of claim 1 , wherein the effective amount of the radionuclide labeled HER3 targeting antibody is a maximum tolerated dose.
9 . The method of claim 1 , wherein the radionuclide labeled HER3 targeting agent is 225 Ac-labeled, and the effective amount of the 225 Ac-labeled HER3 targeting antibody comprises a dose of 0.1 to 50 μCi/kg body weight of the subject, or 0.1 to 5 μCi/kg body weight of the subject, or 5 to 20 μCi/kg subject body weight.
10 . The method of claim 1 , wherein the radionuclide labeled HER3 targeting antibody is 225 Ac-labeled, and the effective amount of the 225 Ac-labeled HER3 targeting agent comprises a dose of 2 μCi to 2mCi, or 2 μCi to 250 μCi, or 75 μCi to 400 μCi.
11 . The method of claim 1 , wherein the effective amount of the radionuclide labeled HER3 targeting antibody comprises a protein dose of less than 3 mg/kg body weight of the subject, such as from 0.001 mg/kg patient weight to 3.0 mg/kg patient weight, or from 0.005 mg/kg patient weight to 2.0 mg/kg patient weight, or from 0.01 mg/kg patient weight to 1 mg/kg patient weight, or from 0.1 mg/kg patient weight to 0.6 mg/kg patient weight, or 0.3 mg/kg patient weight, or 0.4 mg/kg patient weight, or 0.5 mg/kg patient weight, or 0.6 mg/kg patient weight.
12 . The method of claim 1 , wherein the radionuclide labeled HER3 targeting antibody is administered according to a dosing schedule selected from the group consisting of once every 7, 10, 12, 14, 20, 24, 28, 36, and 42 days throughout a treatment period, wherein the treatment period includes at least two doses.
13 . The method of claim 1 , further comprising:
administering to the subject a therapeutically effective amount of a DNA damage response inhibitor (DDRi), a chemotherapeutic agent, or any combination thereof.
14 . The method of claim 1 , further comprising:
administering to the subject a therapeutically effective amount of an immune checkpoint therapy comprising an antibody against PD-1, PD-L1, CTLA-4, or any combination thereof.
15 . The method of claim 1 , wherein the radionuclide labeled HER3 targeting antibody comprises a chemically conjugated chelator group that chelates a radionuclide.
16 . The method of claim 15 , wherein the chelator group comprises DOTA.
17 . The method of claim 1 , wherein the administering step comprises:
administering to the subject a therapeutically effective amount of a therapeutic composition comprising a radiolabeled fraction of the HER3 targeting antibody and a non-radiolabeled fraction of the HER3 targeting antibody.
18 . The method of claim 17 , wherein the therapeutic composition further comprises at least one pharmaceutically acceptable excipient.
19 . The method of claim 1 , further comprising the step of: diagnosing the subject with HER3-positive cancer prior to the administering step.
20 . The method of claim 19 , wherein the diagnosing step comprises imaging HER3-positive cells in the subject using a radionuclide labeled HER3 targeting antibody.
21 . The method of claim 1 , wherein the radionuclide labeled HER3 targeting antibody is
225 Ac labeled p-SCN-Bn-DOTA conjugated barecetamab.
22 . The method of claim 21 , wherein the solid cancer is ovarian cancer, breast cancer, prostate cancer, non-small cell lung cancer, gastric cancer, or pancreatic cancer.
23 . The method of claim 1 , wherein the radionuclide labeled HER3 targeting antibody is
225 Ac labeled p-SCN-Bn-DOTA conjugated patritumab.
24 . The method of claim 23 , wherein the solid cancer is ovarian cancer, breast cancer, prostate cancer, non-small cell lung cancer, gastric cancer, or pancreatic cancer.
25 . The method of claim 1 , wherein the radionuclide labeled HER3 targeting antibody is
225 Ac labeled p-SCN-Bn-DOTA conjugated seribantumab.
26 . The method of claim 25 , wherein the solid cancer is ovarian cancer, breast cancer, prostate cancer, non-small cell lung cancer, gastric cancer, or pancreatic cancer.
27 . The method of claim 1 , wherein the radionuclide labeled HER3 targeting antibody is
225 Ac labeled p-SCN-Bn-DOTA conjugated lumretuzumab.
28 . The method of claim 27 , wherein the solid cancer is ovarian cancer, breast cancer, prostate cancer, non-small cell lung cancer, gastric cancer, or pancreatic cancer.
29 . The method of claim 1 , wherein the radionuclide labeled HER3 targeting antibody is
225 Ac labeled p-SCN-Bn-DOTA conjugated elgemtumab.
30 . The method of claim 29 , wherein the solid cancer is ovarian cancer, breast cancer, prostate cancer, non-small cell lung cancer, gastric cancer, or pancreatic cancer.
31 . The method of claim 1 , wherein the radionuclide labeled HER3 targeting antibody is
a 225 Ac labeled p-SCN-Bn-DOTA conjugated antibody comprising an immunoglobulin heavy chain variable region comprising a CDR-H1 comprising SEQ ID NO:15, a CDR-H2 comprising SEQ ID NO: 16, and a CDR-H3 comprising SEQ ID NO:17, and an immunoglobulin light chain variable region comprising a CDR-L1 comprising SEQ ID NO:18, a CDR-L2 comprising SEQ ID NO:19, and a CDR-L3 comprising SEQ ID NO:20;
a 225 Ac labeled p-SCN-Bn-DOTA conjugated antibody comprising an immunoglobulin heavy chain variable region comprising SEQ ID NO:21 and an immunoglobulin light chain variable region comprising SEQ ID NO:22; or
a 225 Ac labeled p-SCN-Bn-DOTA conjugated antibody comprising an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:23 and an immunoglobulin light chain amino acid sequence of SEQ ID NO:24.
32 . The method of claim 31 , wherein the solid cancer is ovarian cancer, breast cancer, prostate cancer, non-small cell lung cancer, gastric cancer, or pancreatic cancer.