Radioconjugates directed to MHC-complexed antigens in cancer
View Patent ↗Radionuclide-labeled soluble biologics directed against peptide presenting Major Histocompatibility Complexes (pMHCs), and methods for treating cancers using the biologics are provided. Soluble biologics include recombinant T-cell receptor proteins (rTCR) and TCR-antibody mimics that specifically bind to pMHCs. The soluble biologics may further include a heavy chain of IgG1, IgG2, IgG4, or variants thereof. The radioisotopes used to label the soluble biologic may include alpha-emitting isotopes, such as actinium-225, or beta-emitting isotopes, such as lutetium-177, and may be administered at a maximum tolerated dose in a single bolus or in fractionated doses that together equal the maximum tolerated dose. The methods may further include administration of additional therapeutic agents or modalities.
1. A method for treating a cancer in a human subject, comprising administering a composition consisting essentially of an effective amount of a radiolabeled antibody comprising:
an antibody component comprising the complementarity determining regions (CDRs):
CDR H1 comprising amino acid sequence
(SEQ ID NO: 177)
DYAMH,
CDR H2 comprising amino acid sequence
(SEQ ID NO: 178)
GISWNSGSIGYADSVKG,
CDR H3 comprising amino acid sequence
(SEQ ID NO: 179)
GRGFHYYYYGMDI,
CDR L1 comprising amino acid sequence
(SEQ ID NO: 180)
GGNNIGSRSVH,
CDR L2 comprising amino acid sequence
(SEQ ID NO: 181)
DDSDRPS, and
CDR L3 comprising amino acid sequence
(SEQ ID NO: 182)
QVWDSRTDHWV;
a chelator chemically conjugated to the antibody component, wherein the chelator is DOTA or a DOTA derivative; and
225 Ac radionuclide chelated by the chelator.
2. The method of claim 1 , wherein the antibody has been conjugated to DOTA by reaction of the unconjugated antibody with p-SCN-Bn-DOTA.
3. The method of claim 1 , wherein the cancer is breast cancer, metastatic breast cancer, tamoxifen-resistant breast cancer, triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), colorectal cancer, bladder cancer, head and neck carcinoma, endometrial cancer, hepatocellular carcinoma, melanoma, or cutaneous melanoma.
4. A method for treating a cancer in a human subject, comprising administering a composition consisting essentially of an effective amount of a radiolabeled antibody comprising:
an antibody component comprising the complementarity determining regions (CDRs):
CDR H1 comprising amino acid sequence
(SEQ ID NO: 177)
DYAMH,
CDR H2 comprising amino acid sequence
(SEQ ID NO: 178)
GISWNSGSIGYADSVKG,
CDR H3 comprising amino acid sequence
(SEQ ID NO: 179)
GRGFHYYYYGMDI,
CDR L1 comprising amino acid sequence
(SEQ ID NO: 180)
GGNNIGSRSVH,
CDR L2 comprising amino acid sequence
(SEQ ID NO: 181)
DDSDRPS, and
CDR L3 comprising amino acid sequence
(SEQ ID NO: 182)
QVWDSRTDHWV;
a chelator chemically conjugated to the antibody component, wherein the chelator is DOTA or a DOTA derivative; and
225 Ac radionuclide chelated by the chelator,
wherein the antibody has been conjugated to DOTA by reaction of the unconjugated antibody with p-SCN-Bn-DOTA, and
wherein the cancer is breast cancer, metastatic breast cancer, tamoxifen-resistant breast cancer, triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), colorectal cancer, bladder cancer, head and neck carcinoma, endometrial cancer, hepatocellular carcinoma, melanoma, or cutaneous melanoma.