Novel therapeutic antibodies for the treatment and prevention of AIDS

用于治疗和预防艾滋病的新型治疗性抗体

• 批准号: 8329488
• 负责人: Bill Don Harriman
• 金额: $ 19.48万
• 依托单位: CRYSTAL BIOSCIENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8329488
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Address; Ally; Antibodies; Antibody Formation; Binding; Biological; Biological Assay; Blocking Antibodies; CCR5 gene; Cell Communication; Cell surface; Cells; Chemokine (C-C Motif) Receptor 5; Chickens; Clinical; Detection; Development; Disease; Disease Progression; Docking; Down-Regulation; Epitope Mapping; Epitopes; Evolution; Extracellular Domain; Failure; HIV; Hematopoietic; High Prevalence; Human; Immune response; In Vitro; Individual; Infection; Life; Longitudinal Studies; Mammalian Cell; Membrane; Modality; Monoclonal Antibodies; Mucous Membrane; Mus; Passive Immunization; Passive Immunotherapy; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Problem Solving; Proteins; Series; Structure; Surface; Technology; Testing; Therapeutic; Therapeutic antibodies; Vaccines; Viral; Viral Load result; Viral Proteins; Viral Vaccines; Virus; Virus Diseases; Virus Receptors; Woman; extracellular; in vitro Model; innovation; member; men; novel therapeutics; polyclonal antibody; pre-clinical; prevent; programs; prophylactic; receptor; response; success; theories; transcytosis; transmission process

DESCRIPTION (provided by applicant): We seek to capitalize on a substantial body of work has characterized the immune responses of HIV+ individuals with very slow disease progression (LTNP), and HIV- individuals who do not seroconvert despite repeated HIV exposure (ESN). A fraction of people in these groups produce natural anti-CCR5 antibodies that are associated with their disease-free status (in longitudinal studies loss of these antibodies results in disease progression). These antibodies are unique in that they bind a rare CCR5 epitope, induce a long term downregulation of CCR5 on the surface of cells, and can inhibit transcytosis of HIV across mucosal membranes. Experimentally raised polyclonal chicken antibodies to this epitope are even more potent than their human-derived counterparts with respect to these biological activities, and represent an opportunity to develop a unique product offering in the HIV/AIDS arena. We will use our proprietary technology to raise a panel of chicken monoclonal antibodies to this CCR5 epitope and humanize the most active members of this panel for further development. PUBLIC HEALTH RELEVANCE: An estimated 33.4 million people worldwide are now living with HIV, and 2.7 million are newly infected every year, with a higher prevalence among women, as women are biologically more vulnerable to HIV than men. Anti-viral drugs have proven effective in allowing HIV+ individuals to live longer disease-free lives. However, this success has done little to reduce the spread of HIV/AIDS worldwide, since it does not address HIV transmission between individuals. In principle, vaccines can solve this problem, although many years of intense effort have not yielded a product. The difficulty is to some extent due to the ability of HIV, more so than other viruses, to rapidly evolve and therefore evade a vaccine-centric immune response that is restricted by the physical structure of the vaccine itself. Furthermore, it is well known that HIV+ individuals produce antibodies to viral proteins, but generally these antibodies do not slow the progression of disease. For these reasons, a new strategy has emerged: to identify blocking antibodies against the HIV receptors or co-receptors, such as CCR5, rather than the virus itself. The receptors/co-receptors are native human proteins that HIV requires, but does not genetically control. However, since receptors are "self" proteins, it is unlikely that a vaccine approach will reliably generate a vigorous response in humans. The alternative is to develop potent antibodies independently in other species, and use humanized versions of them in the modality of passive immunotherapy. Antibodies that block HIV infection could potentially be used therapeutically in HIV+ individuals to reduce viral load and disease progression, and could also be used prophylactic ally to reduce transmission between individuals if present in the appropriate mucosal tissues. An innovative approach using a humanized chicken monoclonal antibody to a cryptic epitope on the HIV co- receptor CCR5 is anticipated to yield a candidate that is superior to other CCR5 antibodies in preclinical or clinicl development.

描述（由申请人提供）：我们寻求利用大量的工作，这些工作表征了疾病进展非常缓慢的HIV+个体（LTNP）和尽管反复暴露于HIV但未发生血清转化的HIV-个体（ESN）的免疫应答。这些人群中的一小部分人产生与其无病状态相关的天然抗CCR 5抗体（在纵向研究中，这些抗体的丢失导致疾病进展）。这些抗体的独特之处在于它们结合罕见的CCR 5表位，诱导细胞表面上CCR 5的长期下调，并且可以抑制HIV跨粘膜的转胞吞作用。实验性产生的针对该表位的多克隆鸡抗体在这些生物活性方面甚至比它们的人源对应物更有效，并且代表了在HIV/AIDS竞技场中开发独特产品的机会。我们将使用我们的专有技术，以提高一组鸡单克隆抗体的CCR 5表位和人源化的最活跃的成员，这个小组的进一步发展。 公共卫生关系：据估计，全世界目前有3 340万人感染艾滋病毒，每年有270万人新感染，其中妇女的感染率更高，因为妇女在生理上比男子更容易感染艾滋病毒。抗病毒药物已被证明可以有效地使艾滋病毒阳性个体活得更长的无病生活。然而，这一成功对减少艾滋病毒/艾滋病在全世界的传播没有起到什么作用，因为它没有解决艾滋病毒在人与人之间的传播。原则上，疫苗可以解决这个问题，尽管多年的努力还没有产生一种产品。这种困难在某种程度上是由于艾滋病毒比其他病毒更有能力快速进化，从而逃避疫苗本身物理结构限制的以疫苗为中心的免疫反应。此外，众所周知，HIV+个体产生针对病毒蛋白的抗体，但通常这些抗体不会减缓疾病的进展。出于这些原因，出现了一种新的策略：识别针对HIV受体或辅助受体（如CCR 5）的阻断抗体，而不是病毒本身。受体/辅助受体是HIV需要的天然人类蛋白质，但不受遗传控制。然而，由于受体是“自身”蛋白质，因此疫苗方法不太可能在人体中可靠地产生强烈的反应。另一种方法是在其他物种中独立开发有效的抗体，并在被动免疫疗法中使用它们的人源化版本。阻断HIV感染的抗体可潜在地用于治疗HIV+个体以减少病毒载量和疾病进展，并且如果存在于适当的粘膜组织中，也可预防性地用于减少个体之间的传播。预期使用针对HIV共受体CCR 5上的隐蔽表位的人源化鸡单克隆抗体的创新方法产生在临床前或临床开发中上级其他CCR 5抗体的候选物。