Off-target binding of an anti-amyloid beta monoclonal antibody to platelet factor 4 causes acute and chronic toxicity in cynomolgus monkeys
| Autor: | Andreas Popp, Alexander Ibraghimov, Lise I. Loberg, Stefan Barghorn, Lili Huang, Meha Chhaya, Andreas Striebinger, Frank Oellien, Edit Tarcsa |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
a-beta oligomer
Male Time Factors cross-reactivity Pharmacology medicine.disease_cause Platelet Factor 4 Cross-reactivity 0302 clinical medicine Antibody Specificity Immunology and Allergy Toxicity Tests Chronic Chronic toxicity 0303 health sciences Mice Inbred BALB C biology nonspecific binding 030220 oncology & carcinogenesis Toxicity Antibody biotherapeutic Female Antibody heparin-induced thrombocytopenia Blood Platelets Alzheimer Vaccines medicine.drug_class Amyloid beta Immunology Monoclonal antibody Antibodies Monoclonal Humanized Immunity Heterologous Risk Assessment off-target binding 03 medical and health sciences In vivo Report medicine Toxicity Tests Acute Animals Humans 030304 developmental biology No-Observed-Adverse-Effect Level Purpura Thrombocytopenic Idiopathic Amyloid beta-Peptides business.industry Platelet Activation amyloid beta Macaca fascicularis biology.protein adverse effects business polyspecificity Platelet factor 4 |
| Zdroj: | mAbs article-version (VoR) Version of Record |
| ISSN: | 1942-0870 1942-0862 |
| Popis: | ABT-736 is a humanized monoclonal antibody generated to target a specific conformation of the amyloid-beta (Aβ) protein oligomer. Development of ABT-736 for Alzheimer’s disease was discontinued due to severe adverse effects (AEs) observed in cynomolgus monkey toxicity studies. The acute nature of AEs observed only at the highest doses suggested potential binding of ABT-736 to an abundant plasma protein. Follow-up investigations indicated polyspecificity of ABT-736, including unintended high-affinity binding to monkey and human plasma protein platelet factor 4 (PF-4), known to be involved in heparin-induced thrombocytopenia (HIT) in humans. The chronic AEs observed at the lower doses after repeat administration in monkeys were consistent with HIT pathology. Screening for a backup antibody revealed that ABT-736 possessed additional unintended binding characteristics to other, unknown factors. A subsequently implemented screening funnel focused on nonspecific binding led to the identification of h4D10, a high-affinity Aβ oligomer binding antibody that did not bind PF-4 or other unintended targets and had no AEs in vivo. This strengthened the hypothesis that ABT-736 toxicity was not Aβ target-related, but instead was the consequence of polyspecificity including PF-4 binding, which likely mediated the acute and chronic AEs and the HIT-like pathology. In conclusion, thorough screening of antibody candidates for nonspecific interactions with unrelated molecules at early stages of discovery can eliminate candidates with polyspecificity and reduce potential for toxicity caused by off-target binding. |
| Databáze: | OpenAIRE |
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