Formation, clearance, deposition, pathogenicity, and identification of biopharmaceutical-related immune complexes: review and case studies.
Vascular inflammation, infusion reactions, glomerulopathies, and other potentially adverse effects may be observed in laboratory animals, including monkeys, on toxicity studies of therapeutic monoclonal antibodies and recombinant human protein drugs. Histopathologic and immunohistochemical (IHC) evaluation suggests these effects may be mediated by deposition of immune complexes (ICs) containing the drug, endogenous immunoglobulin, and/or complement components in the affected tissues. ICs may be observed in glomerulus, blood vessels, synovium, lung, liver, skin, eye, choroid plexus, or other tissues or bound to neutrophils, monocytes/macrophages, or platelets. IC deposition may activate complement, kinin, and/or coagulation/fibrinolytic pathways and result in a systemic proinflammatory response. IC clearance is biphasic in humans and monkeys (first from plasma to liver and/or spleen, second from liver or spleen). IC deposition/clearance is affected by IC composition, immunomodulation, and/or complement activation. Case studies are presented from toxicity study monkeys or rats and indicate IHC-IC deposition patterns similar to those predicted by experimental studies of IC-mediated reactions to heterologous protein administration to monkeys and other species. The IHC-staining patterns are consistent with findings associated with generalized and localized IC-associated pathology in humans. However, manifestations of immunogenicity in preclinical species are generally not considered predictive to humans.
Charles River Pathology Associates, Frederick, Maryland, USA jennifer.rojko@crl.com.
Jennifer L
JL
Rojko
Pfizer, Inc, San Diego, California, USA.
Mark G
MG
Evans
Charles River Pathology Associates, Frederick, Maryland, USA.
Shari A
SA
Price
Pfizer, Inc, San Diego, California, USA.
Bora
B
Han
CSL Limited, Parkville, Melbourne, Australia.
Gary
G
Waine
CSL Behring, King of Prussia, Pennsylvania, USA.
Mark
M
DeWitte
CSL Limited, Parkville, Melbourne, Australia.
Jill
J
Haynes
Peregrine Pharmaceuticals, Inc, Tustin, California, USA.
Bruce
B
Freimark
Janssen, Malvern, Pennsylvania, USA.
Pauline
P
Martin
Charles River Pathology Associates, Frederick, Maryland, USA.
James T
JT
Raymond
Pfizer, Inc, San Diego, California, USA.
Winston
W
Evering
MedImmune, Gaithersburg, Maryland, USA.
Marlon C
MC
Rebelatto
MedImmune, Gaithersburg, Maryland, USA.
Emanuel
E
Schenck
bluebird bio, Cambridge, Massachusetts, USA.
Christopher
C
Horvath
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D003176:Complement C3 / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D000882:Haplorhini; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D051381:Rats; D014652:Vascular Diseases / Q000139:chemically induced / Q000473:pathology*
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D003176:Complement C3; D015938:Complement Membrane Attack Complex; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C047610:SC5b-9 protein complex
glomerular disease.; hypersensitivity reactions; immune complex pathology; immunohistochemistry; infusion reactions; monkeys; vascular inflammation