Single Dose Toxicity Study of Humanized Anti-HER2 Antibody Drug Conjugate in Rats
- VernacularTitle: 抗HER2靶点抗体偶联药物大鼠单次给药毒性研究
- Author:
Xin WANG
1
Author Information
- Publication Type:Journal Article
- Keywords: Acute toxicity; Antibody drug conjugate; DM1; HER2 target; Rat
- From: Chinese Pharmaceutical Journal 2020;55(2):96-104
- CountryChina
- Language:Chinese
- Abstract: OBJECTIVE: To conduct a single dose toxicology study of humanized anti-HER2 antibody drug conjugate for injection (HS630) and small molecular maytansine (DM1) in Sprague-Dawley rats. METHODS: Rats were divided randomly into nine groups including HS630 blank control group (0 mg•kg-1), DM1 vehicle control group (0 mg•kg-1), positive control group (Kadcyla®, 60 mg•kg-1), HS630 low-, middle-, high-dose groups (6, 20, 60 mg•kg-1) and DM1 low-, middle-, high-dose groups (0.10, 0.20, 0.40 mg•kg-1). Each group had twenty rats with female and male in half. Each rat was administered intravenously once. Animals were observed clinical symptoms consisting of behavior, fur and feces daily as well as body weight and food consumption twice or three times per week. Dissection was executed at D2 and D21 to examine gross anatomy with histopathological changes and weight main tissues. RESULTS: Rats given 60 mg•kg-1 HS630 appeared some adverse effects that 1/20 animal was dead. It was found that maximal tolerance dose of HS630 was 20 mg•kg-1 equivalent to 0.34 mg•kg-1 DM1. High dose could lead body weight and food consumption reduced and organ weights changed including liver, kidney, spleen and lung increased and testicle and epididymis decreased. Histopathological changes were observed in liver, spleen, lung, thymus, pancreas, kidney, mesenteric glands, intestinum, seminal vesicle, prostate, testicle, epididymis, adrenal gland, thyroid gland, pituitary body, eye, tongue, sternum (marrow), bone, skin, injection site. Rats given Kadcyla® showed the similar side effects with HS630. Rats given 20 mg•kg-1 HS630, abnormality weren′t observed in clinical symptom, body weight and food consumption. It could lead kidney and lung weighted. Histopathological changes were found in liver, spleen, thymus, pancreas, lung, kidney, mesenteric glands, duodenum, adrenal gland, pituitary body, skin. Rats given DM1 exhibited worse adverse effects that 2/20 animals were dead at 0.40 mg•kg-1 level. The maximal tolerance dose of DM1 was 0.20 mg•kg-1. High dose could lead body weight and food consumption reduced and organ weights changed including liver, spleen and adrenal gland increased and thymus decreased. Histopathological changes were found in liver, spleen, thymus, kidney, mesenteric glands, duodenum, intestinum, seminal vesicle, adrenal gland, pituitary body, eye, tongue, sternum (marrow), bone, skin. CONCLUSION: Rats given single dose of humanized anti-HER2 antibody-drug conjugate for injection (HS630) and chemical maytansine (DM1) respectively, the RESULTS: show that HS630, a kind of ADC products, have similar toxicological profile with Kadcyla® and exhibit better tolerability and wider safety margin when given the comparable dosage with DM1 based on the RESULTS: of tolerance, clinical symptoms, organ weight and histopathological findings.
