Trispecific monoclonal antibody for botulinum neurotoxin intoxication therapy
用于肉毒杆菌神经毒素中毒治疗的三特异性单克隆抗体
基本信息
- 批准号:8839870
- 负责人:
- 金额:$ 43.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-06-20 至 2017-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAllergic ReactionAmino Acid SequenceAntibodiesAntibody TherapyAntitoxinsAwardBindingBinding SitesBiological AssayBiotechnologyBioterrorismBlood CirculationBontoxilysinBotulinum Toxin Type ABotulismClinicalClinical TrialsContractsCyclic GMPDrug KineticsEpitopesEquus caballusEventFDA approvedFundingGoalsGrantHalf-LifeHumanImmunoglobulin Variable RegionIncidenceIndividualIntensive CareIntoxicationMonoclonal AntibodiesMusPharmaceutical PreparationsPhase I Clinical TrialsPositioning AttributePreventionProductionPropertyProteinsQuality ControlRecombinant AntibodyRelative (related person)SerotypingSerumTestingTherapeutic EffectToxic effectToxinWorkabstractingbasebiothreatbotulinum toxin type Bbotulinum toxin type Ecostcost effectivehigh riskhuman diseasein vivoneutralizing monoclonal antibodiessafety testingstoichiometry
项目摘要
Abstract
The goal of this project is to generate highly potent trispecific antibodies for the prevention and
treatment of botulism due to botulinum neurotoxins (BoNT) serotypes A, B, E, and F. BoNTs are one of the six
highest-risk threat agents for bioterrorism, due to their extreme potency and lethality, ease of production, and
need for prolonged intensive care. Equine antitoxin has a high incidence of allergic reactions, a short serum
half-life leading to reintoxication, is challenging to administer, and cannot be given prophylactically. Given the
extraordinary toxicity of BoNTs, antitoxin must be of very high potency. Previous studies have found that no
single mAb neutralizes BoNT with the requisite potency, however combining mAbs binding non-overlapping
epitopes leads to highly potent BoNT neutralization due to rapid clearance of BoNT from the circulation.
We have generated combinations of three mAbs that bind all subtypes of BoNT/A, B, or E and result in
highly potent BoNT neutralization in vivo. Based on the potency, HHS has awarded contracts to a
biotechnology company (XOMA (US) LLC) to develop these mAb combinations for clinical use. The BoNT/A
three mAb combination has entered phase 1 clinical trials. The BoNT/B and BoNT/E three mAb combinations
are in cGMP manufacturing and will enter clinical trials by 2013-2014. A challenge of this approach is the large
number of mAbs that need to be manufactured and quality controlled (3 per serotype). This adds to the cost
and complexity of the product, especially if the mAbs are all going to be combined to create a multi-serotype
drug. Our proposed alternative is to create a single trispecific mAb for each serotype incorporating the binding
sites of each of the three mAbs. For this work, we hypothesize that such trispecific mAb can be generated
which will have the same binding and BoNT neutralization properties as the three mAb combination.
In the R21 portion we will construct trispecific antibodies (TsAbs) binding three non-overlapping
BoNT/A epitopes. Four different TsAbs will be constructed that differ with respect to where each of the three
variable domains are positioned relative to the antibody Fc. Each TsAb will be characterized and optimized
with respect to affinity for each of the three epitopes, stoichiometry of binding to BoNT/A, stability, and ease of
expression and purification. Multiple TsAb constructs will be evaluated for in vivo pharmacokinetics (PK) and
BoNT/A clearance and neutralization potency in the mouse neutralization assay. In vivo studies will be
conducted at the USDA by our long-term collaborator, Dr. Luisa Cheng. These studies will identify those
constructs with optimal properties and will result in a single mAb that potently neutralizes BoNT/A. In the R33
portion of this grant, the optimal construct identified for BoNT/A will be applied to three other BoNT serotypes,
B, E and F. The result of this project will be antibodies that would treat over 99% of human botulism cases.
摘要
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)
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James D. Marks其他文献
Predictors of All-Cause 30-Day Readmissions in Patients with Heart Failure at an Urban Safety Net Hospital: The Importance of Social Determinants of Health and Mental Health
- DOI:
10.1016/j.ajmo.2023.100060 - 发表时间:
2023-12-01 - 期刊:
- 影响因子:
- 作者:
Alexandra B. Steverson;Paul J. Marano;Caren Chen;Yifei Ma;Rachel J. Stern;Jean Feng;Efstathios D. Gennatas;James D. Marks;Matthew S. Durstenfeld;Jonathan D. Davis;Priscilla Y. Hsue;Lucas S. Zier - 通讯作者:
Lucas S. Zier
Factors affecting perioperative pulmonary function in acute respiratory failure.
急性呼吸衰竭围手术期肺功能影响因素
- DOI:
- 发表时间:
1990 - 期刊:
- 影响因子:9.6
- 作者:
Diane R. Biery;Diane R. Biery;James D. Marks;James D. Marks;A. Schapera;A. Schapera;M. Autry;M. Autry;R. M. Schlobohm;R. M. Schlobohm;Jeffrey A. Katz;Jeffrey A. Katz - 通讯作者:
Jeffrey A. Katz
Mass spectral analysis of a protein complex using single-chain antibodies selected on a peptide target: applications to functional genomics.
使用针对肽靶标选择的单链抗体对蛋白质复合物进行质谱分析:在功能基因组学中的应用。
- DOI:
10.1006/jmbi.2000.4070 - 发表时间:
2000 - 期刊:
- 影响因子:5.6
- 作者:
Robert W. Siegel;Beth Allen;P. Pavlík;James D. Marks;Andrew Bradbury;Andrew Bradbury - 通讯作者:
Andrew Bradbury
Internalizing antibodies and targeted cancer therapy: direct selection from phage display libraries.
内化抗体和靶向癌症治疗:从噬菌体展示库中直接选择。
- DOI:
10.1016/s1461-5347(00)00280-7 - 发表时间:
2000 - 期刊:
- 影响因子:0
- 作者:
Ulrik Nielsen;James D. Marks - 通讯作者:
James D. Marks
James D. Marks的其他文献
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{{ truncateString('James D. Marks', 18)}}的其他基金
Renewable antibodies to secreted proteins and single and multi-pass cell surface
针对分泌蛋白以及单次和多次细胞表面的可再生抗体
- 批准号:
8702409 - 财政年份:2014
- 资助金额:
$ 43.83万 - 项目类别:
Generation of therapeutic antibodies to serotype F botulism
针对血清型 F 肉毒杆菌中毒的治疗性抗体的产生
- 批准号:
8608996 - 财政年份:2013
- 资助金额:
$ 43.83万 - 项目类别:
Generation of therapeutic antibodies to serotype F botulism
针对血清型 F 肉毒杆菌中毒的治疗性抗体的产生
- 批准号:
8996674 - 财政年份:2013
- 资助金额:
$ 43.83万 - 项目类别:
Generation of therapeutic antibodies to serotype F botulism
针对血清型 F 肉毒杆菌中毒的治疗性抗体的产生
- 批准号:
8790945 - 财政年份:2013
- 资助金额:
$ 43.83万 - 项目类别:
Generation of therapeutic antibodies to serotype F botulism
针对血清型 F 肉毒杆菌中毒的治疗性抗体的产生
- 批准号:
8474647 - 财政年份:2013
- 资助金额:
$ 43.83万 - 项目类别:
Trispecific monoclonal antibody for botulinum neurotoxin intoxication therapy
用于肉毒杆菌神经毒素中毒治疗的三特异性单克隆抗体
- 批准号:
8469825 - 财政年份:2012
- 资助金额:
$ 43.83万 - 项目类别:
Trispecific monoclonal antibody for botulinum neurotoxin intoxication therapy
用于肉毒杆菌神经毒素中毒治疗的三特异性单克隆抗体
- 批准号:
8367214 - 财政年份:2012
- 资助金额:
$ 43.83万 - 项目类别:
Trispecific monoclonal antibody for botulinum neurotoxin intoxication therapy
用于肉毒杆菌神经毒素中毒治疗的三特异性单克隆抗体
- 批准号:
8875583 - 财政年份:2012
- 资助金额:
$ 43.83万 - 项目类别:
Development of botulinum neurotoxin immunotherapy, serotypes C, D, F, and G
肉毒杆菌神经毒素免疫疗法(血清型 C、D、F 和 G)的开发
- 批准号:
8547992 - 财政年份:2012
- 资助金额:
$ 43.83万 - 项目类别:
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