ATR-107

Sprague-Dawley (Crl:CD[SD]) (male and female, 7 to 9 weeks old, ≥170 g)^[1]

10 mg/kg; 50 mg/kg; 250 mg/kg (i.v.); 10 mg/kg; 250 mg/kg (s.c.)

i.v.; weekly; 13 weeks; s.c.; weekly; 13 weeks

Caused 1 female death on day 16 due to marked midzonal to diffuse bridging liver necrosis at 10 mg/kg i.v. At end of dosing phase, induced moderate to marked diffuse bridging liver fibrosis with parenchymal nodules, single-cell hepatocyte necrosis, vacuolation, pigment-laden macrophages, bile duct hyperplasia/degeneration/necrosis, and eosinophil-rich mixed inflammation in 2 males and 2 females, and elevated ALT (70-109 IU/L), AST (194-383 IU/L), and AP (239-281 IU/L) in 3 males at 10 mg/kg i.v. At end of recovery phase, resulted in minimal to moderate diffuse bridging fibrosis in 1 male and 4 females, and elevated ALT (115 IU/L), AST (251 IU/L), and AP (186 IU/L) in 1 male at 10 mg/kg i.v. Induced 100% ADA incidence (log titers >4.74) at end of dosing and recovery phases at 10 mg/kg i.v. Showed no ATR-107-related liver findings, mortality, or clinical pathology changes at 50 mg/kg, 250 mg/kg i.v., and 10 mg/kg, 250 mg/kg s.c. Resulted in 33.3% ADA incidence at 50 mg/kg i.v., 0% at 250 mg/kg i.v., 100% at 10 mg/kg s.c., and 66.7% at 250 mg/kg s.c. at end of dosing phase. Increased serum ATR-107 exposures with dose at i.v. routes. Had lower serum ATR-107 exposure at 250 mg/kg s.c. than at 50 mg/kg i.v.

Sprague-Dawley (Crl:CD[SD]) (female, 7 to 9 weeks old, ≥170 g)^[1]

1 mg/kg; 10 mg/kg

i.v.; weekly; up to 4 doses

Caused no mortality, but elevated ALT (189-1329 IU/L) and AST (294-2079 IU/L) first detected on day 15 (after 3rd dose) in 9/20 and 3/20 rats respectively, values returned to control levels by day 20 then re-elevated in 2/10 rats on day 22 (after 4th dose) at 1 mg/kg i.v. Induced liver microscopic findings (hepatocellular degeneration/necrosis, eosinophilic cytoplasmic droplets, mixed cell inflammation with slight bile duct hyperplasia) after 3 or 4 doses, with necrotic areas and cytoplasmic droplets immunopositive for rat IgG, IgM, and C3 at 1 mg/kg i.v. Detected ADAs at low titers prior to 3rd dose, with high titers (2.75 to >4.74 log titer) in all rats after 3 or 4 doses, and sharp drop in serum ATR-107 concentrations after 3rd dose at 1 mg/kg i.v. Led to 1 female elective euthanasia on day 22 after 4 doses, with marked midzonal hepatocellular necrosis and eosinophilic cytoplasmic droplets at 10 mg/kg i.v. Detected elevated ALT (170-220 IU/L) in 2/20 rats on day 15 (after 3rd dose) and 1/10 rats on day 22 (after 4th dose) at 10 mg/kg i.v. Observed liver microscopic findings (hepatocellular degeneration/necrosis, eosinophilic cytoplasmic droplets) after 4 doses in 1/10 rats, with immunopositivity for rat IgG, IgM, and C3 in affected areas at 10 mg/kg i.v. Detected ADAs in 7/10 rats after 3 doses and 9/10 rats after 4 doses, with measurable but lower serum ATR-107 concentrations after 3rd/4th doses compared to earlier doses at 10 mg/kg i.v.

Crl:CD-1 (ICR) (male and female, 7 to 9 weeks old, ~22 g)^[1]

0.1 mg/kg; 1 mg/kg; 10 mg/kg; 250 mg/kg (i.v.); 10 mg/kg; 250 mg/kg (s.c.)

i.v.; weekly; up to 4 doses (dosing discontinued after 2 or 3 doses in 1 mg/kg i.v. group); s.c.; weekly; up to 4 doses

Caused dose-dependent anaphylactic mortality after ≥2 weekly i.v. doses, with a bell-shaped incidence curve centered at 1 mg/kg i.v. (20/76 animals at 1 mg/kg, 5/76 at 0.1 mg/kg, 4/76 at 10 mg/kg, 1/76 at 250 mg/kg). Induced clinical signs (decreased motor activity, convulsions, ataxia, dyspnea, hunched posture, cool to touch, ptosis, tachypnea, bradypnea) within 4 minutes to 1 hour of dosing at all i.v. doses. Observed mild to moderate pulmonary thrombi with increased intravascular neutrophils in some 1 mg/kg i.v. animals that died. Showed no ATR-107-related body weight, food consumption, or macroscopic/microscopic findings in surviving animals (except clinical signs in 0.1 and 1 mg/kg i.v. groups) at i.v. doses. Resulted in 77% (54/70) ADA incidence at 0.1 mg/kg i.v., 73% (41/56) at 1 mg/kg i.v., 7% (5/71) at 10 mg/kg i.v., and 0% (0/74) at 250 mg/kg i.v. Showed no mortality, clinical signs, or ATR-107-related findings at 10 mg/kg and 250 mg/kg s.c. Resulted in 22% (16/74) ADA incidence at 10 mg/kg s.c. and 0% (0/70) at 250 mg/kg s.c.

Cynomolgus Monkey (male and female, ~3 to 5 years old, ~2 to 6 kg)^[1]

10 mg/kg; 30 mg/kg; 100 mg/kg (i.v.); 10 mg/kg; 100 mg/kg (s.c.)

i.v.; weekly; 13 weeks; s.c.; weekly; 13 weeks

Caused no ATR-107-related mortality, clinical observations, clinical pathology changes, organ weight changes, or macroscopic/microscopic tissue findings at any dose or route. Resulted in 8.3% ADA incidence at 10 mg/kg i.v., 16.7% at 10 mg/kg s.c., and 0% at all higher i.v. and s.c. doses.