Methods of Using Antibody-Drug-Conjugates
This disclosure provides methods of using antibody-drug-conjugates of formula (I). Specifically, the disclosure provides methods of reducing target-mediated cross-reactivity by using the antibody-drug-conjugates (ADCs) of formula (I). The disclosure also includes methods of using such conjugates in a variety of therapeutic indications, as well as methods of production of such conjugates.
1 . A method of reducing toxicity associated with target-mediated cross-reactivity in a subject by administering an antibody-drug conjugate (ADC) of formula (I) to the subject,
wherein, the ADC of formula (I) is:
wherein W 1 is an antibody binding to an antigen; and
wherein the administering reduces the toxicity in the subject associated with target-mediated cross-reactivity of the ADC.
2 . The method of claim 1 , wherein the antigen is expressed in skin or mucosal epithelium of the subject.
3 . The method of claim 2 , wherein the antigen is selected from the group consisting of nectin-4, TACSTD2, EGFR, ERBB3, glycoprotein non-metastatic melanoma protein B (GPNMB), SLC39A6 (LIV-1), SLITRK6, GUCY2C, MUC1, NaPi2b, and cadherin 3.
4 . The method of claim 1 , wherein the antibody is an anti-nectin-4 antibody.
5 . The method of claim 1 , wherein the antibody is an anti-Tumor Associated Calcium Signal Transducer 2 (TACSTD2) antibody.
6 . The method of claim 1 , wherein the antibody comprising the sequence:
X 1 (fGly′)X 2 Z 20 X 3 Z 30
wherein
Z 20 is either a proline or alanine residue;
Z 30 is a basic amino acid or an aliphatic amino acid;
X 1 may be present or absent and, when present, can be any amino acid,
with the proviso that when the sequence is at the N-terminus of the antibody, X 1 is present; and
X 2 and X 3 are each independently any amino acid.
7 . The method of claim 1 , wherein the antibody is an anti-Muc antibody.
8 . The method of claim 1 , wherein the antibody is an anti-NaPi2b antibody.
9 . The method of claim 1 , wherein the antibody binds to at least one target antigen expressed on a vital organ of the subject.
10 . The method of claim 1 , wherein the toxicity is reduced compared to when the subject is administered an antibody-drug conjugate targeting the same antigen and comprising a linker and a payload different from the ADC of formula (I).
11 . The method of claim 1 , wherein the subject has a cell proliferative disorder.
12 . The method of any one of claims 1 to 11 , wherein the wherein the antibody is an IgG1 antibody.
13 . The method of claim 12 , wherein the antibody is an IgG1 kappa antibody.
14 . The method of any one of claims 1 to 13 , wherein the antibody comprises an fGly′ residue, wherein fGly′ is an amino acid of the antibody coupled at W 1 .
15 . The method of claim 14 , wherein the fGly′ is positioned at or near a C-terminus of a heavy chain constant region of the antibody.
16 . The method of claim 14 , wherein the fGly′ residue is positioned in a light chain constant region of the antibody.
17 . The method of claim 14 , wherein the fGly′ residue is positioned in a heavy chain CH1 region of the antibody.
18 . The method of claim 14 , wherein the fGly′ residue is positioned in a heavy chain CH2 region of the antibody.
19 . The method of claim 14 , wherein the fGly′ residue is positioned in a heavy chain CH3 region of the antibody.
20 . The method of any one of claims 1-19 , wherein the antibody-drug conjugate (ADC) of formula (I) is administered to the subject parenterally.
21 . The method of any one of claims 1-19 , wherein the antibody-drug conjugate (ADC) of formula (I) is administered to the subject non-parenterally.
22 . The method of any one of claims 1-21 , wherein the antibody is a monoclonal antibody.
23 . The method of any one of claims 1-21 , wherein the antibody is a humanized antibody.
24 . The method of any one of claims 1-21 , wherein the drug in the antibody-drug conjugate (ADC) of formula (I) is an anti-cancer drug.
25 . The method of claim 24 , wherein the anti-cancer drug comprises a maytansinoid.
26 . The method of claim 1 , wherein the toxicity is reduced in the subject by at least 2 folds when the ADC of Formula (I) is administered, as compared to administering the subject an antibody-drug conjugate targeting the same antigen and comprising a linker and a payload different from the ADC of formula (I).