Neutralizing human mAbs: study in HIV-exposed babies

中和人类单克隆抗体：对艾滋病毒暴露婴儿的研究

• 批准号: 6696676
• 负责人: HOOSEN COOVADIA
• 金额: $ 27万
• 依托单位: NELSON R MANDELA SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6696676
• 关键词: AIDS education /prevention; Africa; African; HIV infections; biotechnology; breast feeding; clinical research; clinical trial phase I; combination chemotherapy; human pregnant subject; human subject; human therapy evaluation; intramuscular injections; monoclonal antibody; neutralizing antibody; nevirapine; newborn human (0-6 weeks); passive immunization; patient oriented research; pharmacokinetics; vertical transmission; women's health

DESCRIPTION (provided by applicant): In 2001, 800,000 children worldwide became HIV infected, mostly through mother-to-child transmission (MTCT). Most MTCT events occurred in Africa. HIV can be transmitted during gestation, intrapartum, or by breastfeeding. While short courses of antiviral drugs in the perinatal period have significantly decreased MTCT in developing countries, breastfeeding had a negative impact on the benefits of this drug treatment. Breastfeeding can account for a substantial proportion of overall MTCT; however, avoidance of breastfeeding is not a realistic public health option in resource-poor settings such as ours in South Africa. Clearly, postnatal HIV transmission by breast milk needs to be addressed. Our long-range goal is to prevent HIV transmission through breastfeeding by passive immunization with combinations of human neutralizing monoclonal antibodies (nmAbs). We passively administered triple or quadruple combinations of human nmAbs targeting conserved HIV Env epitopes to newborn monkeys before and after oral challenge with chimeric simian-human immunodeficiency viruses (SHIVs) that encoded different HIV envelope genes. Of 31 nmAb-treated infant monkeys, 22 were completely protected. In cultured cells, such nmAbs, isolated from individuals infected with HIV clade B, provided potent cross-clade neutralization of primary HIV clade A, B, C, and D isolates. Thus, we postulate that given their safety and long half-lives in adult volunteers and their efficacy in neonatal monkeys, human nmAbs given at regular, long intervals can protect babies breastfed by HIV-positive mothers during the period of nursing. The goal of this application is to conduct a Phase I trial with human nmAbs in HIV-exposed but uninfected infants. We plan to use a combination of human nmAbs that will have been tested already for safety and pharmacokinetics in adult volunteers and that has been effective in neonatal primates challenged with SHIV, criteria that have been met by human nmAbs F105, 2G12, and 2F5. A fourth nmAb, 4E10, may fulfill these criteria soon - this nmAb is potent, safe, and highly effective in neonatal primates. The Specific Aims are to: 1. Determine the safety of nmAbs given by intramuscular administration to HIV-exposed, but uninfected neonates in a triple (or quadruple) combination regimen. All infants will also receive perinatal nevirapine. 2. Establish the pharmacokinetics of each of the human nmAbs given in the combination regimen. 3. Determine the doses for each nmAb in the combination that provide levels at 14 days capable of achieving greater than or equal too 90% neutralization of autologous maternal HIV isolates. 4. Determine the safety of a multiple dosing regimen to be used in follow-up trials. These studies will lay the groundwork for a Phase III passive immunoprophylaxis trial, in which we will test whether MTCT via breast milk can be reduced safely and whether intrapartum HIV transmission can be lowered also.

描述（由申请人提供）： 2001 年，全世界有 800,000 名儿童感染艾滋病毒，主要是通过母婴传播 (MTCT)。大多数母婴传播事件发生在非洲。 HIV 可以在妊娠、产时或母乳喂养期间传播。虽然围产期短期抗病毒药物疗程显着降低了发展中国家的母婴传播，但母乳喂养对这种药物治疗的益处产生了负面影响。母乳喂养在母婴传播中占很大比例；然而，在南非等资源匮乏的地区，避免母乳喂养并不是一个现实的公共卫生选择。显然，需要解决产后母乳传播艾滋病毒的问题。我们的长期目标是通过结合人类中和单克隆抗体 (nmAb) 进行被动免疫，预防通过母乳喂养传播艾滋病毒。在用编码不同 HIV 包膜基因的嵌合猿-人类免疫缺陷病毒 (SHIV) 进行口服攻击之前和之后，我们被动地向新生猴子施用针对保守 HIV 包膜表位的人类 nmAb 的三重或四重组合。在 31 只接受 nmAb 治疗的幼猴中，22 只得到了完全保护。在培养细胞中，从感染 HIV B 分支的个体中分离出的 nmAb，可以对 HIV 分支 A、B、C 和 D 的初级分离株提供有效的跨分支中和作用。因此，我们假设，鉴于人类 nmAb 在成年志愿者中的安全性和较长的半衰期以及在新生猴子中的功效，定期、长时间间隔给予人类 nmAb 可以保护 HIV 阳性母亲在哺乳期间母乳喂养的婴儿。本申请的目标是在暴露于 HIV 且未感染的婴儿中使用人类 nmAb 进行 I 期试验。我们计划使用人类 nmAb 组合，该组合已经在成年志愿者中进行了安全性和药代动力学测试，并且对受到 SHIV 挑战的新生灵长类动物有效，人类 nmAb F105、2G12 和 2F5 已满足标准。第四种 nmAb，4E10，可能很快就能满足这些标准 - 这种 nmAb 对新生灵长类动物有效、安全且高效。具体目标是： 1. 确定在三重（或四重）联合方案中对暴露于 HIV 且未感染的新生儿进行肌内注射 nmAb 的安全性。所有婴儿还将接受围产期奈韦拉平治疗。 2. 建立联合方案中每种人类 nmAb 的药代动力学。 3. 确定组合中每种 nmAb 的剂量，以在 14 天时提供能够实现大于或等于 90% 的自体母体 HIV 分离株中和的水平。 4. 确定后续试验中使用的多次给药方案的安全性。这些研究将为 III 期被动免疫预防试验奠定基础，在该试验中，我们将测试是否可以安全地减少通过母乳进行的母婴传播，以及是否也可以降低产时艾滋病毒传播。