Document Detail

Non-clinical evaluation of GMA161 - an anti-human CD16 (Fc{gamma}RIII) monoclonal antibody for treatment of autoimmune disorders in CD16 transgenic mice.
MedLine Citation:
PMID:  22025730     Owner:  NLM     Status:  Publisher    
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 anti-histamine 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 also were observed with a murine version of the antibody; and 3) the reaction is driven by the atypical hypersensitivity pathway mediated by PAF.
Meghan M Flaherty; Timothy K Maclachlan; Misty Troutt; Tomas Magee; Nadine Tuaillon; Syd Johnson; Kathryn E Stein; Ezio Bonvini; Laura Andrews; Richard Garman
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-10-24
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  -     ISSN:  1096-0929     ISO Abbreviation:  -     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-10-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Currently at AVEO Pharmaceuticals, Cambridge, MA 02139.
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