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1.
Front Immunol ; 15: 1406353, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38881900

RESUMO

An appropriately designed pharmacokinetic (PK) assay that is sensitive for anti-drug antibody (ADA) impact on relevant exposure is an alternative strategy to understand the neutralizing potential of ADAs. However, guidance on how to develop such PK assays and how to confirm the functional ADA impact on exposure is missing. Here, the PK assay of a T-cell-engaging bispecific antibody, cibisatamab, was developed based on its mechanism of action (MoA). Using critical monoclonal anti-idiotypic (anti-ID) antibody positive controls as ADA surrogates, the impact on exposure was evaluated pre-clinically. In a phase I clinical trial (NCT02324257), initial data suggest that the combination of ADA and PK assays for correlation of the ADA response with cibisatamab exposure. To understand the neutralizing potential of patient-derived ADAs on drug activity, advanced ADA characterization has been performed. Structural binding analysis of ADAs to antibody domains of the drug and its impact on targeting were assessed. For this purpose, relevant patient ADA binding features were identified and compared with the specific monoclonal anti-ID antibody-positive controls. Comparable results of target binding inhibition and similar impacts on exposure suggest that the observed reduction of Cmax and Ctrough levels in patients is caused by the neutralizing potential of ADAs and allows a correlation between ADA response and loss of exposure. Therefore, the described study provides important functional aspects for the development of an appropriately designed PK assay for bispecific antibodies as an alternative option towards understanding the neutralizing ADA impact on exposure.


Assuntos
Anticorpos Biespecíficos , Linfócitos T , Humanos , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Anticorpos Anti-Idiotípicos/imunologia , Anticorpos Neutralizantes/imunologia
2.
Bioanalysis ; 16(10): 431-442, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38497775

RESUMO

Aim: To develop an assay format for detection of total anti-adeno-associated virus 2 (AAV2) antibodies with low capsid material consumption. Methods: An immune complex (IC) assay format was developed. The format is based on the formation of ICs in solution and their subsequent detection using an anti-AAV2 antibody for capture and an antibody against the study species IgG for detection. Results: The feasibility of the IC assay for detection of preexisting and treatment-emergent anti-AAV2 antibodies was demonstrated in cynomolgus monkey and human serum samples, including samples from a preclinical study with AAV2-based therapies. Conclusion: The presented IC assay is an easy-to-perform total anti-AAV2 antibody assay that requires a small amount of unlabeled capsid material and provides an intrinsic specificity control.


[Box: see text].


Assuntos
Anticorpos Antivirais , Dependovirus , Macaca fascicularis , Humanos , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Dependovirus/imunologia , Dependovirus/genética , Capsídeo/imunologia , Complexo Antígeno-Anticorpo/imunologia , Complexo Antígeno-Anticorpo/sangue
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