Type II (tositumomab) anti-CD20 monoclonal antibody out performs type I (rituximab-like) reagents in B-cell depletion regardless of complement activation.
Anti-CD20 monoclonal antibodies (mAbs) are classified into type I (rituximab-like) or type II (tositumomab-like) based on their ability to redistribute CD20 molecules in the plasma membrane and activate various effector functions. To compare type I and II mAbs directly in vivo and maximize Fc effector function, we selected and engineered mAbs with the same mouse IgG(2)a isotype and assessed their B-cell depleting activity in human CD20 transgenic mice. Despite being the same isotype, having similar affinity, opsonizing activity for phagocytosis, and in vivo half-life, the type II mAb tositumomab (B1) provided substantially longer depletion of B cells from the peripheral blood compared with the type I mAb rituximab (Rit m2a), and 1F5. This difference was also evident within the secondary lymphoid organs, in particular, the spleen. Failure to engage complement did not explain the efficacy of the type II reagents because type I mAbs mutated in the Fc domain (K322A) to prevent C1q binding still did not display equivalent efficacy. These results give support for the use of type II CD20 mAbs in human B-cell diseases.
Beers
Stephen A
SA
Tenovus Laboratory, Cancer Sciences Division, Southampton University School of Medicine, General Hospital, Southampton, United Kingdom.
Chan
Claude H T
CH
James
Sonya
S
French
Ruth R
RR
Attfield
Kathrine E
KE
Brennan
Claire M
CM
Ahuja
Anupama
A
Shlomchik
Mark J
MJ
Cragg
Mark S
MS
Glennie
Martin J
MJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics / Q000276:immunology*; D018951:Antigens, CD20 / Q000276:immunology* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D003167:Complement Activation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D015922:Complement C1q / Q000276:immunology / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000235:genetics / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods*; D020125:Mutation, Missense; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; C517507:FcgammaRIIIA protein, mouse; D007127:Immunoglobulin Constant Regions; D017452:Receptors, IgG; D000069283:Rituximab; D015922:Complement C1q