Nonclinical evaluation of GMA161--an antihuman CD16 (FcγRIII) monoclonal antibody for treatment of autoimmune disorders in CD16 transgenic mice.
Fc receptors are a critical component of the innate immune system responsible for the recognition of cross-linked antibodies and the subsequent clearance of pathogens. However, in autoimmune diseases, these receptors play a role in the deleterious action of self-directed antibodies and as such are candidate targets for treatment. GMA161 is an aglycosyl, humanized version of the murine antibody 3G8 that targets the human low-affinity Fcγ receptor III (CD16). As CD16 expression and sequence have high species specificity, preclinical assessments were conducted in mice transgenic for both isoforms of human CD16, CD16A, and CD16B. This transgenic mouse model was useful in transitioning into phase I clinical trials, as it generated positive efficacy data in a relevant disease model and an acceptable single-dose safety profile. However, when GMA161 or its murine parent 3G8 were dosed repeatedly in transgenic mice having both human CD16 isoforms, severe reactions were observed that were not associated with significant cytokine release, nor were they alleviated by antihistamine administration. Prophylactic dosing with an inhibitor of platelet-activating factor (PAF), however, completely eliminated all signs of hypersensitivity. These findings suggest that (1) GMA161 elicits a reaction that is target dependent, (2) immunogenicity and similar adverse reactions were observed with a murine version of the antibody, and (3) the reaction is driven by the atypical hypersensitivity pathway mediated by PAF.
Biologics Research and Development, Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA.
Meghan M
MM
Flaherty
Timothy K
TK
MacLachlan
Misty
M
Troutt
Tomas
T
Magee
Nadine
N
Tuaillon
Syd
S
Johnson
Kathryn E
KE
Stein
Ezio
E
Bonvini
Richard
R
Garman
Laura
L
Andrews
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000188:drug therapy*; D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000188:drug therapy; D017452:Receptors, IgG / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology
D061067:Antibodies, Monoclonal, Humanized; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D007074:Immunoglobulin G; D010972:Platelet Activating Factor; D017452:Receptors, IgG; C572525:GMA-161