Toxicological protein biomarker analysis--an investigative one-week single dose intravenous infusion toxicity and toxicokinetic study in cynomolgus monkeys using an antibody-cytotoxic conjugate against ovarian cancer.
BACKGROUND
Antibody-cytotoxic conjugates are complex novel therapeutic agents whose toxicological properties are not presently well understood. The objective of this study was to identify toxicological markers in serum that correlate with MLN8866 (an antibody-cytotoxic conjugate) exposure and related pathological events in monkeys.


METHODS
Cynomolgus monkeys were treated once with 5, 15, or 30 mg/kg MLN8866 via a 20 min intravenous infusion. MLN8866 exposure (Cmax and AUCO-4 day) was determined by quantifying MLN8866 levels in serum.


RESULTS
The increase in MLN8866 exposure was approximately dose proportional. Two acute phase proteins in serum (serum amyloid A and haptoglobin) were correlated with MLN8866 exposure and toxicological outcomes (e.g., erythropoiesis and leucopoiesis).
Hsieh
Frank Y
FY
Nextcea, Inc., 110 Hartwell Avenue, Lexington, Massachusetts 02421, USA. frank.hsieh@nextcea.com
Tengstrand
Elizabeth
E
Li
Lily Y
LY
Huang
Yuling N
YN
Milton
Mark N
MN
Silverman
Lee
L
Alden
Carl
C
Miwa
Gerald
G
Lee
Frank
F
D000818:Animals; D000906:Antibodies / Q000378:metabolism / Q000633:toxicity*; D015415:Biomarkers; D005260:Female; D006242:Haptoglobins / Q000032:analysis*; D000922:Immunotoxins / Q000633:toxicity*; D007262:Infusions, Intravenous; D008252:Macaca fascicularis; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D000685:Serum Amyloid A Protein / Q000032:analysis*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000906:Antibodies; D015415:Biomarkers; D006242:Haptoglobins; D000922:Immunotoxins; C523921:MLN8866; D000685:Serum Amyloid A Protein