Liver Microvascular Injury and Thrombocytopenia of Antibody-Calicheamicin Conjugates in Cynomolgus Monkeys-Mechanism and Monitoring.
Purpose:Adverse reactions reported in patients treated with antibody-calicheamicin conjugates such as gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin include thrombocytopenia and sinusoidal obstruction syndrome (SOS). The objective of this experimental work was to investigate the mechanism for thrombocytopenia, characterize the liver injury, and identify potential safety biomarkers.Experimental Design:Cynomolgus monkeys were dosed intravenously at 6 mg/m2/dose once every 3 weeks with a nonbinding antibody-calicheamicin conjugate (PF-0259) containing the same linker-payload as gemtuzumab ozogamicin and inotuzumab ozogamicin. Monkeys were necropsied 48 hours after the first administration (day 3) or 3 weeks after the third administration (day 63).Results:PF-0259 induced acute thrombocytopenia (up to 86% platelet reduction) with nadirs on days 3 to 4. There was no indication of effects on megakaryocytes in bone marrow or activation of platelets in peripheral blood. Microscopic evaluation of liver from animals necropsied on day 3 demonstrated midzonal degeneration and loss of sinusoidal endothelial cells (SECs) associated with marked platelet accumulation in sinusoids. Liver histopathology on day 63 showed variable endothelial recovery and progression to a combination of sinusoidal capillarization and sinusoidal dilation/hepatocellular atrophy, consistent with early SOS. Among biomarkers evaluated, there were early and sustained increases in serum hyaluronic acid (HA) that correlated well with serum aspartate aminotransferase and liver microscopic changes, suggesting that HA may be a sensitive diagnostic marker of the liver microvascular injury.Conclusions:These data support the conclusion that target-independent damage to liver SECs may be responsible for acute thrombocytopenia (through platelet sequestration in liver sinusoids) and development of SOS.Clin Cancer Res; 23(7); 1760-70. ©2016 AACR.
Drug Safety Research and Development, Pfizer Inc., Pearl River, New York. magali.guffroy@pfizer.com.
Magali
M
Guffroy
Drug Safety Research and Development, Pfizer Inc., Pearl River, New York.
Hadi
H
Falahatpisheh
Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut.
Kathleen
K
Biddle
Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut.
John
J
Kreeger
Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut.
Leslie
L
Obert
Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut.
Karen
K
Walters
Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut.
Richard
R
Goldstein
Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut.
Germaine
G
Boucher
Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut.
Timothy
T
Coskran
Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut.
William
W
Reagan
Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut.
Danielle
D
Sullivan
Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut.
Chunli
C
Huang
Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut.
Sharon
S
Sokolowski
Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut.
Richard
R
Giovanelli
Oncology-Rinat Research & Development, Pfizer Inc., Pearl River, New York.
Hans-Peter
HP
Gerber
Drug Safety Research and Development, Pfizer Inc., Pearl River, New York.
Martin
M
Finkelstein
Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut.
Nasir
N
Khan
D000617:Aminoglycosides / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D053281:Enediynes / Q000008:administration & dosage / Q000737:chemistry; D000079982:Gemtuzumab; D006801:Humans; D006820:Hyaluronic Acid / Q000097:blood; D018796:Immunoconjugates / Q000008:administration & dosage / Q000009:adverse effects; D000080045:Inotuzumab Ozogamicin; D008099:Liver / Q000187:drug effects; D008252:Macaca fascicularis; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D013921:Thrombocytopenia / Q000139:chemically induced / Q000473:pathology*
D000617:Aminoglycosides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053281:Enediynes; D018796:Immunoconjugates; C074528:calicheamicin T; D006820:Hyaluronic Acid; D000079982:Gemtuzumab; D000080045:Inotuzumab Ozogamicin