Monoclonal antibody homodimers: enhanced antitumor activity in nude mice.
The potential for enhancing antibody potency by increasing avidity was investigated using monoclonal IgG homodimers. Chemically linked dimers were made from a human-murine chimeric monoclonal IgG (ChiBR96) which strongly binds to a variety of breast, lung, ovary, and colon carcinomas. This monoclonal antibody is capable of killing tumor cells directly without complement or effector cells in addition to mediating antibody dependent cellular cytotoxicity and complement dependent cytotoxicity. In this study, we examined the effect of antibody valency on antigen binding and biological efficacy by comparing the IgG dimer (tetravalent) to the monomeric IgG (divalent). The dimer demonstrated 3-4-fold greater binding activity against carcinoma cells than the monomer by enzyme linked immunosorbent assay. Surface plasmon resonance analyses showed that while the ChiBR96 monomer and dimer had similar rates of association on specific antigen, the dimer had a significantly slower rate of dissociation (and therefore a higher affinity constant). Although there was no difference between the monomer and dimer in antibody dependent cellular cytotoxicity and complement dependent cytotoxicity, the dimer demonstrated at least 10 times greater direct tumor cell killing than the monomer. Internalization studies using carcinoma cells pulsed with 125I-labeled antibody showed the ChiBR96 dimer reached higher intracellular levels than the monomer. The relative in vivo antitumor effects of the IgG monomer and dimer were studied in nude mice bearing human lung adenocarcinoma xenografts. The dimer was more effective in slowing tumor progression despite having a shorter serum half-life than the monomer. Increasing the valency of IgG monoclonal antibodies may be a useful approach to enhancing their biological efficacy.
Wolff
E A
EA
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121.
Schreiber
G J
GJ
Cosand
W L
WL
Raff
H V
HV
D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000915:Antibody Affinity / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D014408:Biomarkers, Tumor / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism; D003165:Complement System Proteins / Q000276:immunology; D005260:Female; D006207:Half-Life; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D007074:Immunoglobulin G; D003165:Complement System Proteins