目的 开展注射用重组抗HER2人源化单克隆抗体偶联美登素Ⅰ(HS630)和细胞毒素美登素Ⅰ(DM1)的大鼠单次给药毒性研究。方法 大鼠随机分成9组,包括空白对照组,溶媒对照组,对照药(60 mg·kg^-1,Kadcyla®)组,HS630低(6 mg·kg^-1)、中(20 mg·kg^-1)、高(60 mg·kg^-1)剂量组和DM1低(0.10 mg·kg^-1)、中(0.20 mg·kg^-1)、高(0.40 mg·kg^-1)剂量组,每组20只,雌雄各半。采用尾静脉注射给药,给药1次。每天观察各组大鼠的行为活动、外观被毛、粪便等临床症状,每周2~3次称动物体重和摄食量,分别在给药后第2天和第21天解剖动物进行大体观察、称主要脏器质量、HE染色进行病理学检查。结果 大鼠给予HS630后出现一定程度的毒性反应,60 mg·kg^-1剂量导致1/20只大鼠死亡。大鼠对HS630最大耐受量为20 mg·kg^-1,相当于DM1给药量0.34 mg·kg^-1。给予高剂量60 mg·kg^-1的HS630会引起大鼠体重下降,摄食减少;肝、肾、脾、肺质量增加,睾丸、附睾质量减少;肝、脾、肺(含支气管)、胸腺、胰腺、肾、肠系膜淋巴结、肠、精囊腺、前列腺、睾丸、附睾、肾上腺、甲状腺、垂体、眼球、舌、胸骨(骨髓)、骨、皮肤、注射部位出现病理学改变。这些毒性表现与对照药Kadcyla®组相似。大鼠给予中剂量20 mg·kg^-1的HS630,临床症状未见异常,对体重和摄食量无影响,肾和肺质量增加,肝、脾、胸腺、胰腺、肺(含支气管)、肾、肠系膜淋巴结、十二指肠、肾上腺、垂体、皮肤出现病理学改变。大鼠在给予DM1后出现强烈的毒性反应,0.40 mg·kg^-1剂量导致2/20只大鼠死亡,大鼠对DM1最大耐受量为0.20 mg·kg^-1。给予高剂量0.40 mg·kg^-1的DM1会引起大鼠体重下降,摄食减少;肝、脾、肾上腺质量增加,胸腺质量减少。肝、脾、胸腺、肾、肠系膜淋巴结、十二指肠、空肠、直肠、精囊腺、肾上腺、垂体、眼球、舌、胸骨(骨髓)、骨、皮肤出现病理学改变。结论 大鼠尾静脉分别单次给予HS630和DM1两种受试物,从耐受性、毒性症状、脏器质量、组织病理学检查等方面对实验结果进行比较分析,发现抗体偶联药物HS630的毒性表现与对照药Kadcyla®相同;当给予HS630与DM1相近剂量时,HS630比小分子DM1有更好的体内耐受性和更宽的临床用药安全窗。

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 Ⅰ(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.