A Phase I, Blinded, Placebo-controlled, Dose-escalation Study of the Safety and Pharmacokinetics of XOMA 3AB Administered Intravenously in Healthy Adults

This is a phase I, single-center, placebo-controlled, double-blinded, dose escalation study of anti-botulinum toxin monoclonal antibodies in healthy adult volunteers. Volunteers will be hospitalized in the Johns Hopkins Phase 1 unit during the infusion and until after the 24-hour blood draw. Three escalating dose cohorts of a combination of three anti-botulinum monoclonal antibodies will be evaluated. Each cohort will consist of eight volunteers in which they will receive a single intravenous infusion of active drug or placebo. Placebo will be normal saline. Volunteers will be followed for safety for up to 120 days after infusion depending on dose cohort.

开始日期2011-05-01

申办/合作机构

National Institute of Allergy & Infectious Diseases

100 项与 XOMA-3AB 相关的临床结果

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100 项与 XOMA-3AB 相关的转化医学

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100 项与 XOMA-3AB 相关的专利（医药）

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项与 XOMA-3AB 相关的文献（医药）

2012-11-01·Analytical Biochemistry4区 · 生物学

Engineered domain-based assays to identify individual antibodies in oligoclonal combinations targeting the same protein

4区 · 生物学

Article

作者: M.A. Silberg ; M.T. Tomic ; C. Garcia-Rodriguez ; M. Li ; J. Bettencourt ; X. Pan ; Q. Meng ; R. To ; T. Breece ; D. Lee ; L. Thorner ; F. Conrad ; J.D. Marks ; G. Manzanarez

Quantitation of individual monoclonal antibodies (mAbs) within a combined antibody drug product is required for preclinical and clinical drug development. We have developed two antitoxins, XOMA 3B and XOMA 3E, each consisting of three mAbs that neutralize type B and type E botulinum neurotoxin (BoNT/B and BoNT/E) to treat serotype B and E botulism. To develop mAb-specific binding assays for each antitoxin, we mapped the epitopes of the six mAbs. Each mAb bound an epitope on either the BoNT light chain (LC) or translocation domain (H(N)). Epitope mapping data were used to design LC-H(N) domains with orthogonal mutations to make them specific for only one mAb in either XOMA 3B or XOMA 3E. Mutant LC-H(N) domains were cloned, expressed, and purified from Escherichia coli. Each mAb bound only to its specific domain with affinity comparable to the binding to holotoxin. Further engineering of domains allowed construction of enzyme-linked immunosorbent assays (ELISAs) that could characterize the integrity, binding affinity, and identity of each of the six mAbs in XOMA 3B and 3E without interference from the three BoNT/A mAbs in XOMA 3AB. Such antigen engineering is a general method allowing quantitation and characterization of individual mAbs in a mAb cocktail that bind the same protein.

2012-02-01·Analytical Biochemistry4区 · 生物学

Domain-based assays of individual antibody concentrations in an oligoclonal combination targeting a single protein

4区 · 生物学

Article

作者: M.T. Tomic ; C. Huang ; L. Cao ; F. Conrad ; J.D. Marks ; K. Meyer ; R. To ; J. Bettencourt ; Q. Meng ; M.A. Silberg ; M. Li ; J. Ma ; R. Shimizu

Quantitation of individual monoclonal antibodies (mAbs) within a combined antibody drug product is required for preclinical and clinical drug development, including pharmacokinetic (PK), toxicology, stability, and biochemical characterization studies of such drugs. We have developed an antitoxin, XOMA 3AB, consisting of three recombinant mAbs that potently neutralize the known subtypes of type A botulinum neurotoxin (BoNT/A). The three mAbs bind nonoverlapping BoNT/A epitopes with high affinity. XOMA 3AB is being developed as a treatment for botulism resulting from BoNT/A. To develop antibody-specific assays, we cloned, expressed, and purified BoNT/A domains from Escherichia coli. Each mAb bound only to its specific domain with affinity comparable to the binding to holotoxin. mAb-specific domains were used to develop an enzyme-linked immunosorbent assay (ELISA) for characterization of the integrity and binding activity of the three mAbs in the drug product. An electrochemiluminescence bridging assay that is robust to interference from components in serum was also developed, and we demonstrate that it can be used for PK assays. This type of antigen engineering to generate mAb-specific domains is a general method allowing quantitation and characterization of individual mAbs in a mAb cocktail that binds the same protein and is superior to anti-idiotype approaches.

2011-04-01·Journal of Chromatography A2区 · 化学

Separation of oxidized variants of a monoclonal antibody by anion-exchange

2区 · 化学

Article

作者: Vafa Lahidji ; Carol Huang ; Glen Teshima ; Jacob Kung ; Ming-Xiang Li ; Milan Tomic ; Rahima Danishmand ; Chidi Obi ; Robert To ; Joel Freeberg ; Lauren Thorner

Monoclonal antibodies are subject to a variety of degradation mechanisms, therefore orthogonal techniques are required to demonstrate product quality. In this study, the three individual antibodies comprising a multi-antibody drug product, XOMA 3AB were evaluated by both cation-exchange (CEX) and anion-exchange chromatography (AEX). In contrast to CEX analysis which showed only a single, broad peak for the force-oxidized antibodies, AEX analysis of Ab-A (pI=7.6) revealed two more basic peaks. Ab-B (pI=6.7) bound but exhibited only a single major peak while Ab-C (pI=8.6) flowed through. Peptide mapping LC/MS analysis of the isolated Ab-A fractions demonstrated that the basic peaks resulted from oxidation in a complementary determining region (CDR). Differential scanning calorimetry (DSC) analysis of the oxidized Ab-A species showed a decrease in the Fab melting point for the oxidized species consistent with unfolding of the molecule. Greater/lesser surface exposure of ionic residues resulting from a conformational change provides a likely explanation for the dramatic shift in retention behavior for the Ab-A oxidized variants. Peptide mapping analysis of the Ab-B antibody showed, in contrast to Ab-A, no detectable CDR oxidation. Hence, the lack of separation of oxidized variants in Ab-B can be explained by the absence of CDR oxidation and the associated changes in secondary/tertiary structure which were observed for oxidized Ab-A. In summary, anion-exchange HPLC shows potential as an orthogonal analytical technique for assessing product quality of monoclonal antibody therapeutics. In the case of the XOMA 3AB drug product, two of the antibodies bound and one, Ab-A, exhibited separation of CDR oxidized variants.

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
肉毒中毒	申请上市	美国	National Institute of Allergy & Infectious Diseases	2011-05-01
中毒	临床1期	-	Nanotherapeutics, Inc.	-
中毒	临床1期	-	University of California	-
中毒	临床1期	-	XOMA Royalty Corp.	-