Molecular and Structural Studies of Antibody Diversity Mechanisms

抗体多样性机制的分子和结构研究

基本信息

批准号：
10242126
负责人：
Vaughn Vasil Smider
金额：
$ 39.94万
依托单位：
APPLIED BIOMEDICAL SCIENCE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242126
关键词：
Active Sites Amino Acids Antibodies Antibody Diversity Antibody Formation Antibody Repertoire Antigen Targeting Antigens Area Binding Biochemical Biological Biological Response Modifiers Cattle Cells Cellular Assay Color Complementarity Determining Regions Complex Cysteine Data Diagnostic Diagnostics Research Disulfides Electron Microscopy Enzyme Activation Enzymes Epitopes Event Fab Immunoglobulins Family Flow Cytometry Gene Mutation Genes Genetic Genetic Structures HIV HIV Antibodies HIV-1 Human Immune response Immunization Immunize Immunoglobulin G Immunoglobulin Somatic Hypermutation In Vitro Infectious Agent Investigational Therapies Ion Channel Label Left Length Light Maps Matrix Metalloproteinases Mediating Medicine Metalloproteases Methods Modeling Molecular Molecular Genetics Molecular Structure Mus Mutagenesis Mutate Mutation Pathway interactions Pattern Play Polysaccharides Process Property Proteins Reagent Recombinants Role Site-Directed Mutagenesis Structure Surface System Tertiary Protein Structure Testing Therapeutic Time V(D)J Recombination Vaccine Design Vaccines Vertebrates Viral Virus activation-induced cytidine deaminase antibody engineering antigen binding antigen challenge base combinatorial disulfide bond electron crystallography in vivo insight knob protein neutralizing antibody novel response therapeutic candidate vaccine response

项目摘要

Abstract Antibodies are extremely important as the primary mediators of the immune response to infectious agents and vaccines, but also as recombinant molecules used as therapeutics, diagnostics, and research reagents. Thus, understanding the mechanisms by which antibodies form, bind, and neutralize their targets is very important in multiple biomedical areas. Most vertebrate antibody repertoires form their diversity through V(D)J recombination, where combinatorial rearrangement of V, D, and J genes form a vast repertoire where the complementarity determining regions (CDRs) form a relatively flat binding surface for interaction with antigen. Remarkably, cows appear to have a different mechanism for generating diversity and binding antigen; cow antibodies have particularly long CDR H3 regions, a subset of which can be over 70 amino acids long, which form -ribbon “stalk” and disulfide-bonded “knob” minidomains that protrude far from the typical antibody surface. Remarkably, antibodies from this repertoire can potently and broadly neutralize HIV, whereas normal human or mouse antibody repertoires cannot. Therefore, they have unique abilities to bind and neutralize particularly challenging antigens. Here we propose studies to understand in molecular detail the genetic mechanisms underlying formation of these antibodies, the binding properties of the stalk and knob minidomains, and the unique potential of these antibodes to bind bivalently and bispecifically. These studies will provide insight into mechanisms of viral neutralization generally, and particularly HIV neutralization. Additionally, given the potential of these antibodies to bind recessed epitopes, we will generate additional antibodies against particularly challenging antigens like enzymatic active sites and ion channels. We will employ mutagenesis, binding, and structural methods, as well as cellular assays to evaluate the unique properties of these antibodies. Understanding this novel class of antibodies in detail could provide fundamental insights needed for effective vaccine design as well as discovery and engineering of antibodies against some of the most challenging targets in biomedicine. Similarly, our unique antibodies discovered and characterized in this proposal could eventually become therapeutic candidates themselves.

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Milking the Cow: Cattle-Derived Chimeric Ultralong CDR-H3 Antibodies and Their Engineered CDR-H3-Only Knobbody Counterparts Targeting Epidermal Growth Factor Receptor Elicit Potent NK Cell-Mediated Cytotoxicity.

DOI：
10.3389/fimmu.2021.742418
发表时间：
2021
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Pekar L;Klewinghaus D;Arras P;Carrara SC;Harwardt J;Krah S;Yanakieva D;Toleikis L;Smider VV;Kolmar H;Zielonka S
通讯作者：
Zielonka S

Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows.

DOI：
10.1038/nature23301
发表时间：
2017-08-03
期刊：
Nature
影响因子：
64.8
作者：
Sok D;Le KM;Vadnais M;Saye-Francisco KL;Jardine JG;Torres JL;Berndsen ZT;Kong L;Stanfield R;Ruiz J;Ramos A;Liang CH;Chen PL;Criscitiello MF;Mwangi W;Wilson IA;Ward AB;Smider VV;Burton DR
通讯作者：
Burton DR

Germline-Encoded Positional Cysteine Polymorphisms Enhance Diversity in Antibody Ultralong CDR H3 Regions.

DOI：
10.4049/jimmunol.2200455
发表时间：
2022-12-01
期刊：
JOURNAL OF IMMUNOLOGY
影响因子：
4.4
作者：
Jenkins, Gabrielle Warner;Safonova, Yana;V. Smider, Vaughn
通讯作者：
V. Smider, Vaughn

Evolution of immunogenetic components encoding ultralong CDR H3.

DOI：
10.1007/s00251-023-01305-9
发表时间：
2023-08
期刊：
IMMUNOGENETICS
影响因子：
3.2
作者：
Ott, Jeannine A. A.;Mitchell, Christian;Sheppard, Morgan;Deiss, Thad C. C.;Horton, J. M. Cody;Haakenson, Jeremy K. K.;Huang, Ruiqi;Kelley, Abigail R. R.;Davis, Brian W. W.;Derr, James N. N.;Smider, Vaughn V. V.;Criscitiello, Michael F. F.
通讯作者：
Criscitiello, Michael F. F.

Bos taurus ultralong CDR H3 antibodies.