Efficacy of anti-CD5 F(AB′)2 and FAB′ immunoconjugates in human peripheral blood lymphocyte-reconstituted severe combined immunodeficient mice
| Autor: | Ada H. C. Kung, Fred R. Kohn, Marc Better, Susan L. Bernhard, Dianne M. Fishwild |
|---|---|
| Rok vydání: | 1993 |
| Předmět: |
medicine.drug_class
T-Lymphocytes Immunology Mice SCID Ricin Biology Pharmacology CD5 Antigens Monoclonal antibody Immunoglobulin Fab Fragments Mice Antigen Antigens CD Immunotoxin In vivo medicine Animals Humans Cytotoxic T cell Phytohemagglutinins Gelonin Peritoneal Cavity Plant Proteins Immunotoxins Receptors Interleukin-2 Flow Cytometry Virology Immunoconjugate Transplantation Leukocyte Transfusion Ribosome Inactivating Proteins Type 1 Spleen |
| Zdroj: | International Journal of Immunopharmacology. 15:871-878 |
| ISSN: | 0192-0561 |
| DOI: | 10.1016/0192-0561(93)90004-i |
| Popis: | A human peripheral blood lymphocyte-reconstituted severe combined immunodeficient (hu-PBL-SCID) mouse model was used to compare in vivo efficacy of immunoconjugates directed against the CD5 antigen present on human T-cells. Four anti-CD5 immunoconjugates were tested, composed of chimeric human-mouse (cH65) F(ab′) 2 or Fab′ fragments chemically linked to recombinant gelonin (rGEL) or the 30,000 M r glycoform of ricin A chain (RTA 30 ). Immunoconjugate treatment was initiated ≈3 weeks after PBL transplantation and consisted of five consecutive daily bolus i.v. injections. Efficacy was subsequently assessed by quantitation of human T-cells in spleens, blood and peritoneal lavage fluid using 3-color flow cytometry. cH65 F(ab′) 2 - and cH65 Fab′-rGEL conjugates were essentially equally effective at depleting human T-cells from SCID mouse tissues, suggesting that bivalent binding is not required for efficacy when rGEL is the cytotoxic moiety. Treatment with unconjugated F(ab′) 2 , unconjugated Fab′ or a Fab-rGEL immunoconjugate of irrelevant binding specificity did not result in a significant depletion of T-cells, demonstrating that the cytotoxic moiety and a relevant human T-cell binding moiety are both required for efficacy. In contrast to the results observed with the rGEL conjugates, cH65 Fab′ - RTA 30 was not as effective as cH65 F(ab′) 2 -RTA 30 in depleting human T-cells from SCID mouse tissues. This paralleled in vitro findings in a human PBMC cytotoxicity assay, which demonstrated that cH65 Fab′ - RTA 30 was 17-fold less potent than cH65 F(ab′) 2 -RTA 30 and ≈50-fold less potent than the rGEL conjugates. These results indicate that the hu-PBL-SCID mouse model can be used to evaluate potential differences in efficacy of cytotoxic agents directed against human T-cells and implicate anti-CD5 conjugates containing rGEL as potentially potent therapeutic agents. |
| Databáze: | OpenAIRE |
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