Generation and characterization of a novel tetravalent anti-CD22 antibody with improved antitumor activity and pharmacokinetics.
The purpose of this study was to prepare a tetravalent anti-human CD22 recombinant antibody with improved antitumor activity and a half life longer than that of its divalent counterpart. We compared the ability of tetravalent vs. divalent antibody to associate/dissociate to/from CD22-positive Daudi cells, to interact with murine and human Fcgamma receptors (FcgammaR), to bind human complement component C1q, to inhibit the growth of tumor cells, to diffuse into various tissues, to be internalized by Daudi cells, to react with human neonatal Fc receptors (FcRn), and to persist in the circulation of normal mice. As compared to the murine or chimeric divalent antibodies, the chimeric tetravalent counterpart has a longer half life in mice. It also has an affinity for FcRns that is identical to that of human IgG. The tetravalent antibody has increased antitumor activity in vitro and completely conserved effector functions (binding to FcgammaR-positive cells and to C1q) in vitro. Despite its 33% higher molecular weight, it penetrates mouse tissues as well as its divalent antibody counterpart. Based on the improved in vitro performance and pharmacokinetics of the tetravalent antibody it will now be tested for its antitumor activity in vivo.
Liu
Xiao-Yun
XY
The Cancer Immunobiology Center, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Blvd, NB9.210, Dallas, Texas 75390-8576, USA.
Pop
Laurentiu M
LM
Roopenian
Derry C
DC
Ghetie
Victor
V
Vitetta
Ellen S
ES
Smallshaw
Joan E
JE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D015922:Complement C1q / Q000276:immunology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D011961:Receptors, Fc / Q000235:genetics / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology*; D020298:U937 Cells
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; D017452:Receptors, IgG; D051918:Sialic Acid Binding Ig-like Lectin 2; D015922:Complement C1q; C100688:Fc receptor, neonatal