Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen.
Conjugates of the anti-CanAg humanized monoclonal antibody huC242 with the microtubule-formation inhibitor DM1 (a maytansinoid), or with the DNA alkylator DC1 (a CC1065 analogue), have been evaluated for their ability to eradicate mixed cell populations formed from CanAg-positive and CanAg-negative cells in culture and in xenograft tumors in mice. We found that in culture, conjugates of either drug killed not only the target antigen-positive cells but also the neighboring antigen-negative cells. Furthermore, we showed that, in vivo, these conjugates were effective in eradicating tumors containing both antigen-positive and antigen-negative cells. The presence of antigen-positive cells was required for this killing of bystander cells. This target cell-activated killing of bystander cells was dependent on the nature of the linker between the antibody and the drug. Conjugates linked via a reducible disulfide bond were capable of exerting the bystander effect whereas equally potent conjugates linked via a nonreducible thioether bond were not. Our data offer a rationale for developing optimally constructed antibody-drug conjugates for treating tumors that express the target antigen either in a homogeneous or heterogeneous manner.
Kovtun
Yelena V
YV
ImmunoGen, Inc., Cambridge, Massachusetts 02139, USA. yelena.kovtun@immunogen.com
Audette
Charlene A
CA
Ye
Yumei
Y
Xie
Hongsheng
H
Ruberti
Mary F
MF
Phinney
Sara J
SJ
Leece
Barbara A
BA
Chittenden
Thomas
T
Blättler
Walter A
WA
Goldmacher
Victor S
VS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000276:immunology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D003432:Cross-Linking Reagents / Q000737:chemistry; D005260:Female; D019073:HT29 Cells; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D008453:Maytansine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D003432:Cross-Linking Reagents; D018796:Immunoconjugates; C488736:N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)maytansine; D008453:Maytansine