Functional Deimmunization of Therapeutic Proteins

治疗性蛋白质的功能性去免疫化

基本信息

  • 批准号:
    8290453
  • 负责人:
  • 金额:
    $ 29.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-07-01 至 2016-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The advance of therapeutic proteins represents a revolution in clinical practice, but use of protein drugs requires consideration of their immunogenicity and potential to elicit an anti-biotherapeutic immune response (aBIR) in human patients. Such aBIRs can manifest a range of complications ranging from loss of efficacy to life-threatening anaphylactic shock, and mitigating immunogenicity is a key aspect of biotherapeutic development. While numerous factors influence protein immunogenicity, one critical feature is the source, i.e. proteins of non-human origin are disproportionately immunogenic. Given the immense therapeutic potential of foreign proteins, a variety of deimmunization strategies have been considered. Some methods, such as antibody humanization, are highly effective but limited to a narrow subset of protein classes. Others, such as conjugation to polyethylene glycol, are widely applicable but typically lead to a substantial loss of protein function. Modern protein engineering has enabled genetic approaches wherein immunogenic epitopes are deleted by site-directed mutagenesis, but current methods are costly, time and labor intensive, and have shown limited success. In contrast, computational tools for protein analysis are fast, efficient, and increasingly accurate. In this proposal, it is hypothesized that novel optimization algorithms can be leveraged to design protein variants that simultaneously reduce protein immunogenicity while maintaining high level functionality. Aim 1 will test the hypothesis that for a given therapeutic protein, there exists a predictable and optimizable spectrum of trade-offs between the competing goals of reduced immunogenicity and high-level functionality. Ten engineered variants of a 2-lactamase therapeutic candidate (P992L) will be designed with a range of weights on the two objective functions: deimmunization vs. functionality. The P992L variants will be produced and assayed for activity, thermostability and immunogenicity. Aim 2 will test the hypothesis that combinatorial protein libraries can be computationally optimized for functional therapeutic candidates. The optimization algorithms will be extended to enable design of deimmunized combinatorial protein libraries. Five libraries, having a range of relative weights for deimmunization vs. functionality, will be constructed and screened with a high throughput functional assay. The proportion of library members exhibiting high level functionality will be quantitatively determined, and the results will be benchmarked against the original library design parameters. Aim 3 seeks to evaluate and refine the models of immunogenicity and functionality that underlie the objective functions of the design algorithm. An enhanced model of protein structure will be integrated into the design algorithm, and a new panel of P992L proteins will be constructed and experimentally evaluated. The results of these analyses will subsequently be used to update the optimization objectives and algorithm, and produce new variants, thereby closing the loop between computation and experiment. Successfully achieving these aims will yield broadly applicable algorithms for engineering powerful and immune-tolerant therapeutic proteins.
DESCRIPTION (provided by applicant): The advance of therapeutic proteins represents a revolution in clinical practice, but use of protein drugs requires consideration of their immunogenicity and potential to elicit an anti-biotherapeutic immune response (aBIR) in human patients. Such aBIRs can manifest a range of complications ranging from loss of efficacy to life-threatening anaphylactic shock, and mitigating immunogenicity is a key aspect of biotherapeutic development. While numerous factors influence protein immunogenicity, one critical feature is the source, i.e. proteins of non-human origin are disproportionately immunogenic. Given the immense therapeutic potential of foreign proteins, a variety of deimmunization strategies have been considered. Some methods, such as antibody humanization, are highly effective but limited to a narrow subset of protein classes. Others, such as conjugation to polyethylene glycol, are widely applicable but typically lead to a substantial loss of protein function. Modern protein engineering has enabled genetic approaches wherein immunogenic epitopes are deleted by site-directed mutagenesis, but current methods are costly, time and labor intensive, and have shown limited success. In contrast, computational tools for protein analysis are fast, efficient, and increasingly accurate. In this proposal, it is hypothesized that novel optimization algorithms can be leveraged to design protein variants that simultaneously reduce protein immunogenicity while maintaining high level functionality. Aim 1 will test the hypothesis that for a given therapeutic protein, there exists a predictable and optimizable spectrum of trade-offs between the competing goals of reduced immunogenicity and high-level functionality. Ten engineered variants of a 2-lactamase therapeutic candidate (P992L) will be designed with a range of weights on the two objective functions: deimmunization vs. functionality. The P992L variants will be produced and assayed for activity, thermostability and immunogenicity. Aim 2 will test the hypothesis that combinatorial protein libraries can be computationally optimized for functional therapeutic candidates. The optimization algorithms will be extended to enable design of deimmunized combinatorial protein libraries. Five libraries, having a range of relative weights for deimmunization vs. functionality, will be constructed and screened with a high throughput functional assay. The proportion of library members exhibiting high level functionality will be quantitatively determined, and the results will be benchmarked against the original library design parameters. Aim 3 seeks to evaluate and refine the models of immunogenicity and functionality that underlie the objective functions of the design algorithm. An enhanced model of protein structure will be integrated into the design algorithm, and a new panel of P992L proteins will be constructed and experimentally evaluated. The results of these analyses will subsequently be used to update the optimization objectives and algorithm, and produce new variants, thereby closing the loop between computation and experiment. Successfully achieving these aims will yield broadly applicable algorithms for engineering powerful and immune-tolerant therapeutic proteins.

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Chris Bailey-Kellogg其他文献

Chris Bailey-Kellogg的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Chris Bailey-Kellogg', 18)}}的其他基金

Deimmunized Griffithsin Microbicide
去免疫格里菲辛杀菌剂
  • 批准号:
    9919030
  • 财政年份:
    2019
  • 资助金额:
    $ 29.4万
  • 项目类别:
Engineering a Potent Immune-evading Uricase
设计一种有效的免疫逃避尿酸酶
  • 批准号:
    9908607
  • 财政年份:
    2019
  • 资助金额:
    $ 29.4万
  • 项目类别:
Design and Development of Immunotolerant S. aureus Biotherapies
免疫耐受金黄色葡萄球菌生物疗法的设计和开发
  • 批准号:
    9253183
  • 财政年份:
    2015
  • 资助金额:
    $ 29.4万
  • 项目类别:
Computationally optimized anti-staphylococcal biotherapeutics
计算优化的抗葡萄球菌生物疗法
  • 批准号:
    8415825
  • 财政年份:
    2012
  • 资助金额:
    $ 29.4万
  • 项目类别:
Computationally optimized anti-staphylococcal biotherapeutics
计算优化的抗葡萄球菌生物疗法
  • 批准号:
    8226022
  • 财政年份:
    2012
  • 资助金额:
    $ 29.4万
  • 项目类别:
Functional Deimmunization of Therapeutic Proteins
治疗性蛋白质的功能性去免疫化
  • 批准号:
    8706904
  • 财政年份:
    2011
  • 资助金额:
    $ 29.4万
  • 项目类别:
Functional Deimmunization of Therapeutic Proteins
治疗性蛋白质的功能性去免疫化
  • 批准号:
    8158955
  • 财政年份:
    2011
  • 资助金额:
    $ 29.4万
  • 项目类别:
Functional Deimmunization of Therapeutic Proteins
治疗性蛋白质的功能性去免疫化
  • 批准号:
    8892201
  • 财政年份:
    2011
  • 资助金额:
    $ 29.4万
  • 项目类别:
Functional Deimmunization of Therapeutic Proteins
治疗性蛋白质的功能性去免疫化
  • 批准号:
    8502706
  • 财政年份:
    2011
  • 资助金额:
    $ 29.4万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 29.4万
  • 项目类别:
    Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 29.4万
  • 项目类别:
    Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 29.4万
  • 项目类别:
    Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 29.4万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 29.4万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 29.4万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 29.4万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 29.4万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 29.4万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 29.4万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了