Tumor targeting with newly designed biparatopic antibodies directed against two different epitopes of the carcinoembryonic antigen (CEA).


Autoria(s): Robert B.; Dorvillius M.; Buchegger F.; Garambois V.; Mani J.C.; Pugnières M.; Mach J.P.; Pèlegrin A.
Data(s)

1999

Resumo

In an attempt to improve tumor targeting and tumor retention time of monoclonal antibodies (MAbs), we prepared biparatopic antibodies (BpAbs) having the capability of binding 2 different non-overlapping epitopes on the same target antigen molecule, namely, the carcinoembryonic antigen (CEA). Six BpAbs were constructed by coupling 2 different Fab' fragments from 4 different specific anti-CEA MAbs recognizing 4 CEA epitopes (Gold 1-4). Demonstration of the double paratopic binding of these antibodies for CEA was confirmed in vitro by inhibition radioimmunoassay and cross-inhibition analysis by surface plasmon resonance (SPR; BIACORE) technology. Using the latter technique, the affinity constants for CEA immobilized onto the sensor chip were found to range from 0.37 to 1.54 x 10(9) M(-1) for the 4 parental F(ab')2 fragments and from 1.88 to 10.14 x 10(9) M(-1) for the BpAbs, demonstrating the advantage of biparatopic binding over conventional F(ab')2 binding. The Ka improvement was particularly high for BpAb F6/35A7 and BpAb F6/B17 with a 9.5- and 8.1-fold increase, respectively, as compared with the parental F(ab')2. In vivo, the 6 BpAbs were compared with their 2 respective parental F(ab')2 by injection of 131I-BpAb/125I-F(ab')2 parental fragments into nude mice xenografted with the human colon carcinoma T380. Dissection 72 hr post-injection demonstrated that BpAb B17/CE25 and BpAb F6/B17 gave higher tumor uptake than that of their parental F(ab')2. This finding is particularly interesting for BpAb F6/B17, which compared favorably with the F6 F(ab')2, one of the best parental F(ab')2 fragments used in our study.

Identificador

http://serval.unil.ch/?id=serval:BIB_ECAB66E8C1A0

isbn:0020-7136 (Print)

pmid:10188732

doi:10.1002/(SICI)1097-0215(19990412)81:2<285::AID-IJC19>3.0.CO;2-T

isiid:000079283600019

Idioma(s)

en

Fonte

International Journal of Cancer, vol. 81, no. 2, pp. 285-291

Palavras-Chave #Animals; Antibodies, Bispecific/immunology; Antibodies, Monoclonal; Carcinoembryonic Antigen/immunology; Epitopes/immunology; Humans; Immunoglobulin Fab Fragments/immunology; Kinetics; Mice; Mice, Nude; Transplantation, Heterologous; Tumor Cells, Cultured
Tipo

info:eu-repo/semantics/article

article