Off-target binding of an anti-amyloid beta monoclonal antibody to platelet factor 4 causes acute and chronic toxicity in cynomolgus monkeys
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 AE...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2021-01-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2021.1887628 |
| _version_ | 1798040789987622912 |
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| author | Lise I. Loberg Meha Chhaya Alexander Ibraghimov Edit Tarcsa Andreas Striebinger Andreas Popp Lili Huang Frank Oellien Stefan Barghorn |
| author_facet | Lise I. Loberg Meha Chhaya Alexander Ibraghimov Edit Tarcsa Andreas Striebinger Andreas Popp Lili Huang Frank Oellien Stefan Barghorn |
| author_sort | Lise I. Loberg |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T22:12:32Z |
| format | Article |
| id | doaj.art-54871d30e40440c9ae5713239f79f81b |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-04-11T22:12:32Z |
| publishDate | 2021-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-54871d30e40440c9ae5713239f79f81b2022-12-22T04:00:31ZengTaylor & Francis GroupmAbs1942-08621942-08702021-01-0113110.1080/19420862.2021.1887628Off-target binding of an anti-amyloid beta monoclonal antibody to platelet factor 4 causes acute and chronic toxicity in cynomolgus monkeysLise I. Loberg0Meha Chhaya1Alexander Ibraghimov2Edit Tarcsa3Andreas Striebinger4Andreas Popp5Lili Huang6Frank Oellien7Stefan Barghorn8Development Sciences, AbbVie Inc., North Chicago, IL, USAGlobal Biologics, AbbVie Inc., Worcester, MA, USAPreclinical Safety, AbbVie Inc., Worcester, MA, USADMPK-BA, AbbVie Inc., Worcester, MA, USADiscovery Biology, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, GermanyPreclinical Safety, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, GermanyGlobal Biologics, AbbVie Inc., Worcester, MA, USADiscovery Chemistry, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, GermanyDiscovery Biology, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, GermanyABT-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.https://www.tandfonline.com/doi/10.1080/19420862.2021.1887628Antibody biotherapeuticplatelet factor 4adverse effectsoff-target bindingnonspecific bindingpolyspecificity |
| spellingShingle | Lise I. Loberg Meha Chhaya Alexander Ibraghimov Edit Tarcsa Andreas Striebinger Andreas Popp Lili Huang Frank Oellien Stefan Barghorn Off-target binding of an anti-amyloid beta monoclonal antibody to platelet factor 4 causes acute and chronic toxicity in cynomolgus monkeys mAbs Antibody biotherapeutic platelet factor 4 adverse effects off-target binding nonspecific binding polyspecificity |
| title | Off-target binding of an anti-amyloid beta monoclonal antibody to platelet factor 4 causes acute and chronic toxicity in cynomolgus monkeys |
| title_full | Off-target binding of an anti-amyloid beta monoclonal antibody to platelet factor 4 causes acute and chronic toxicity in cynomolgus monkeys |
| title_fullStr | Off-target binding of an anti-amyloid beta monoclonal antibody to platelet factor 4 causes acute and chronic toxicity in cynomolgus monkeys |
| title_full_unstemmed | Off-target binding of an anti-amyloid beta monoclonal antibody to platelet factor 4 causes acute and chronic toxicity in cynomolgus monkeys |
| title_short | Off-target binding of an anti-amyloid beta monoclonal antibody to platelet factor 4 causes acute and chronic toxicity in cynomolgus monkeys |
| title_sort | off target binding of an anti amyloid beta monoclonal antibody to platelet factor 4 causes acute and chronic toxicity in cynomolgus monkeys |
| topic | Antibody biotherapeutic platelet factor 4 adverse effects off-target binding nonspecific binding polyspecificity |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2021.1887628 |
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