Table 6.
In vivo studies for anti-amyloid β mAb.
| Species | Study | Dose/s | Group sex and size | Findings |
|---|---|---|---|---|
| APP-transgenic mouse model | Histopathological evaluation of select tissues in a pharmacology study. | 0.5 mg/mouse/ week (ip) | 15M/group; 7-11 animals/group available for histopathological evaluation | Histological changes (neoplasia, renal changes, degenerative joint disease, skeletal muscle de/re-generation) were considered due to aging or potential background changes in mouse strain and not due to antibody treatment. |
| APP-transgenic mouse model | 4 week GLP toxicology | 0 mg/kg (iv and sc) | 12M+12F/group and 6M+6F recovery/group and 18M+18F TK satellites/group. Plus additional TK groups for control and 200 mg/kg (iv) with 12 weeks treatment. | Up to 200 mg/kg for 4 weeks was well tolerated. 200 mg/kg for 12 weeks was well tolerated in animals for TK analysis. Anti-drug antibodies were detected in 62% of antibody-dosed animals. |
| 60 mg/kg (iv) | NOAEL = 200 mg/kg. | |||
| 200 mg/kg (sc) | ||||
| 200 mg/kg (iv) | ||||
| Cynomolgus monkey | PK study | 5 mg/kg single dose (iv and sc) | t ½ ∼8 d. Low clearance and volume of distribution. No adverse or notable effects observed. | |
| Cynomolgus monkey | 13 week GLP toxicology | 0 mg/kg (iv and sc) | 5M+5F | Low doses (20 and 60 mg/kg): Thrombocytopenia (decreased platelets), pulmonary vasculature changes (medial hypertrophy, thrombosis), lung findings (multifocal hemorrhages, interstitial fibrosis). |
| 20 mg/kg (iv) | 120 mg/kg (iv) 1M | High doses (120 and 200 mg/kg): Acute infusion reaction (5-10 min post-dose) with lethal consequence at 200 mg/kg. | ||
| 60 mg/kg (iv and sc) | 200 mg/kg (iv) 4M | |||
| 120 mg/kg (iv) | ||||
| 200 mg/kg (iv) | ||||
| Cynomolgus monkey | Exploratory toxicity study | 0 mg/kg (iv bolus) | 1M+1F | IV infusion (1 hour) produced a less severe acute infusion reaction compared with iv bolus administration at the same dose level. Acute infusion reaction ≥ 60 mg/kg included complement activation. No effects on cytokines, coagulation factors or ECG's. Histopathologic effects observable after 4 weeks of dosing (thrombotic and/or arterial changes in brain, lung and injection sites). |
| 2 mg/kg (iv bolus) | NOAEL = 2 mg/kg | |||
| 60 mg/kg (iv bolus) | ||||
| 120 mg/kg (iv infusion or bolus) | ||||
| 200 mg/kg (iv infusion) |