In vivo efficacy of monoclonal antibody-drug conjugates of three different subisotypes which bind the human tumor-associated antigen defined by the KS1/4 monoclonal antibody.
A panel of three hybridomas has been isolated each of which secretes a single species of monoclonal antibody (MoAb) directed against the KS1/4 tumor-associated antigen originally described by Varki et al. (Cancer Res 44: 681, 1984). These MoAbs were designated L1-(IgG2b), L2-(IgG1), and L4-(IgG2a)KS. Binding specificity, immuno-precipitation, and competitive binding analyses indicated that these MoAbs each recognize the same epitope of the KS1/4 antigen. The immunoprecipitation studies indicated that the MoAbs recognized a major antigenic component of 42 kDa and a minor component of 35 kDa. The L-KS antibodies were evaluated as MoAb-drug conjugates against a variety of human tumor targets grown in vivo as nude mouse xenografts. The MoAb-drug conjugates were constructed using protein-A-purified MoAbs conjugated to 4-desacetyl-vinblastine-3-carbohydrazide. Efficacy was determined using various dosing protocols on 2-14 day established tumors of lung, pharynx, colon, and skin origin. Control experiments included the use of dual-flank antigen-positive and negative tumors, free MoAbs, free drug, and mixtures of MoAbs and drug. These studies indicated that significant tumor growth suppression and actual tumor regression could be achieved by the MoAb-vinca conjugates and that this activity was antigen-mediated. The drug conjugates were more efficacious than free drug or free MoAbs administered either singly or in combination with each other.
Starling
J J
JJ
Research Laboratories, Eli Lilly and Co., Indianapolis, IN 46285.
Maciak
R S
RS
Hinson
N A
NA
Nichols
C L
CL
Briggs
S L
SL
Laguzza
B C
BC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000918:Antibody Specificity; D000951:Antigens, Neoplasm / Q000276:immunology*; D001666:Binding Sites, Antibody; D001667:Binding, Competitive; D002460:Cell Line; D006801:Humans; D006825:Hybridomas / Q000032:analysis; D007126:Immunoglobulin Allotypes / Q000008:administration & dosage; D000922:Immunotoxins / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011233:Precipitin Tests; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives*
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D007126:Immunoglobulin Allotypes; D000922:Immunotoxins; C055170:4-desacetylvinblastine hydrazide; D014747:Vinblastine