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，全球80万名儿童感染了艾滋病毒，主要是通过母亲到孩子传播（MTCT）。大多数MTCT事件发生在非洲。 hiv可以在妊娠，胸腔内或通过母乳喂养传播。尽管在发展中国家，在围产期期间，抗病毒药物的简短课程显着降低，但母乳喂养对这种药物治疗的益处产生了负面影响。母乳喂养可以占整体MTCT的很大比例；但是，避免母乳喂养并不是我们在南非等资源贫乏的环境中的现实公共卫生选择。显然，需要解决产后艾滋病毒的传播。我们的远距离目标是通过被动免疫与人类中和单克隆抗体（NMABS）的结合来防止通过母乳喂养传播HIV。我们通过用嵌合邻近的诸如替代型诸如替代性的诸如替代猴子的免疫缺陷病毒（SHIV）（SHIV）靶向保守的HIV HIV ENV属性的人NMAB的三重或四倍组合，该猴子在口腔挑战之前和之后。在31 nmab处理的婴儿猴子中，有22只受到了完全保护。在培养的细胞中，从感染HIV进化枝B的个体中分离出的这种NMAB，提供了原发性HIV A，B，C和D分离株的有效的跨层中和中和。因此，我们假设他们在成年志愿者中的安全性和长期衰老及其在新生儿猴子中的疗效，因此在护理期间，定期以长时间间隔给予的人NMAB可以保护艾滋病毒阳性母亲母乳喂养的婴儿。该应用的目的是在艾滋病毒暴露但未感染的婴儿中对人NMAB进行I期试验。我们计划使用人类NMAB的组合，这些人的NMAB已经在成人志愿者的安全性和药代动力学中进行了测试，并且在受SHIV挑战的新生儿灵长类动物中有效，这是由人类NMABS F105、2G12和2F5满足的标准。第四个NMAB 4E10可能很快就会符合这些标准 - 该NMAB在新生儿灵长类动物中具有有效，安全且非常有效。具体目的是：1。确定肌肉内给药给出的NMAB的安全性，以hiv暴露但未感染的新生儿三重（或四倍）组合方案。所有婴儿还将接受围产期奈韦拉平。 2。建立组合方案中每种人类NMAB的药代动力学。 3。确定组合中每种NMAB的剂量，该剂量在14天后提供水平，能够实现自体母体HIV分离株的超过或相等90％的中和。 4。确定要在后续试验中使用的多种剂量方案的安全性。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降低MTCT，以及是否还可以降低产前HIV的传播。