In vivo antitumor activity of a monoclonal antibody-Vinca alkaloid immunoconjugate directed against a solid tumor membrane antigen characterized by heterogeneous expression and noninternalization of antibody-antigen complexes.
It is widely believed that antigen heterogeneity and noninternalization of antigen-antibody complexes will severely limit the antitumor activity of monoclonal antibody-drug conjugates. The B72.3 monoclonal antibody binds to a tumor-associated antigen which is heterogeneously expressed in human carcinomas (J. Schlom, Cancer Res., 46: 3225-3238, 1986). We therefore performed studies to assess the degree of internalization of B72.3 antibody-antigen complexes and the level of in vivo antitumor activity that could be achieved with B72.3 conjugated to 4-desacetyl vinblastine-3-carboxhydrazide. Internalization studies were performed on LS174T colorectal carcinoma and OVCAR-3 ovarian carcinoma cells using iodinated B72.3 as well as an iodinated antibody that binds to the human transferrin receptor, IIB21. These data indicated that, in contrast to HB-21, the B72.3 antigen-antibody complex was not internalized. The B72.3-Vinca alkaloid immunoconjugate demonstrated significant antitumor activity against LS174T xenografts, although complete regressions of established tumors were not achieved. Immunohistochemical analyses indicated that the B72.3 antigen was heterogeneously expressed in the LS174T xenografts and that tumor cells which were not killed by high doses of B72.3-Vinca also expressed the B72.3 antigen. These studies indicated that significant antitumor activity may be achieved by monoclonal antibody-drug conjugates even when antigen heterogeneity and noninternalization of antigen-antibody complexes are encountered. The data also suggested that the formulation of antibody-drug conjugate cocktails to counteract antigen heterogeneity may not be sufficient to eradicate all malignant cells within a solid tumor mass.
Starling
J J
JJ
Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana 46285.
Maciak
R S
RS
Law
K L
KL
Hinson
N A
NA
Briggs
S L
SL
Laguzza
B C
BC
Johnson
D A
DA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D000922:Immunotoxins / Q000378:metabolism* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D013696:Temperature; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use
C052417:4-desacetylvinblastine-monoclonal antibody KS1-4 conjugate; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D006023:Glycoproteins; D000922:Immunotoxins; C047052:tumor-associated antigen 72; D014747:Vinblastine