PMID- 33596779
OWN - NLM
STAT- MEDLINE
DCOM- 20211104
LR  - 20240226
IS  - 1942-0870 (Electronic)
IS  - 1942-0862 (Print)
IS  - 1942-0862 (Linking)
VI  - 13
IP  - 1
DP  - 2021 Jan-Dec
TI  - Off-target binding of an anti-amyloid beta monoclonal antibody to platelet factor 
      4 causes acute and chronic toxicity in cynomolgus monkeys.
PG  - 1887628
LID - 10.1080/19420862.2021.1887628 [doi]
LID - 1887628
AB  - ABT-736 is a humanized monoclonal antibody generated to target a specific 
      conformation of the amyloid-beta (Abeta) 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 Abeta 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 Abeta 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.
FAU - Loberg, Lise I
AU  - Loberg LI
AUID- ORCID: 0000-0002-6478-9480
AD  - Development Sciences, AbbVie Inc ., North Chicago, IL, USA.
FAU - Chhaya, Meha
AU  - Chhaya M
AD  - Global Biologics, AbbVie Inc ., Worcester, MA, USA.
FAU - Ibraghimov, Alexander
AU  - Ibraghimov A
AD  - Preclinical Safety, AbbVie Inc ., Worcester, MA, USA.
FAU - Tarcsa, Edit
AU  - Tarcsa E
AD  - DMPK-BA, AbbVie Inc ., Worcester, MA, USA.
FAU - Striebinger, Andreas
AU  - Striebinger A
AD  - Discovery Biology, AbbVie Deutschland GmbH & Co. KG , Ludwigshafen, Germany.
FAU - Popp, Andreas
AU  - Popp A
AD  - Preclinical Safety, AbbVie Deutschland GmbH & Co. KG , Ludwigshafen, Germany.
FAU - Huang, Lili
AU  - Huang L
AD  - Global Biologics, AbbVie Inc ., Worcester, MA, USA.
FAU - Oellien, Frank
AU  - Oellien F
AD  - Discovery Chemistry, AbbVie Deutschland GmbH & Co. KG , Ludwigshafen, Germany.
FAU - Barghorn, Stefan
AU  - Barghorn S
AD  - Discovery Biology, AbbVie Deutschland GmbH & Co. KG , Ludwigshafen, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - MAbs
JT  - mAbs
JID - 101479829
RN  - 0 (Alzheimer Vaccines)
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 37270-94-3 (Platelet Factor 4)
SB  - IM
MH  - Alzheimer Vaccines/*immunology/pharmacokinetics/toxicity
MH  - Amyloid beta-Peptides/*antagonists & inhibitors/immunology
MH  - Animals
MH  - Antibodies, Monoclonal, Humanized/immunology/pharmacokinetics/*toxicity
MH  - Antibody Specificity
MH  - Blood Platelets/*drug effects/immunology/metabolism
MH  - Female
MH  - Humans
MH  - *Immunity, Heterologous
MH  - Macaca fascicularis
MH  - Male
MH  - Mice, Inbred BALB C
MH  - No-Observed-Adverse-Effect Level
MH  - Platelet Activation/drug effects
MH  - Platelet Factor 4/*antagonists & inhibitors/immunology
MH  - Purpura, Thrombocytopenic, Idiopathic/blood/*chemically induced/immunology
MH  - Risk Assessment
MH  - Time Factors
MH  - Toxicity Tests, Acute
MH  - Toxicity Tests, Chronic
MH  - Mice
PMC - PMC7894423
OTO - NOTNLM
OT  - Antibody biotherapeutic
OT  - a-beta oligomer
OT  - adverse effects
OT  - amyloid beta
OT  - cross-reactivity
OT  - heparin-induced thrombocytopenia
OT  - nonspecific binding
OT  - off-target binding
OT  - platelet factor 4
OT  - polyspecificity
EDAT- 2021/02/19 06:00
MHDA- 2021/11/05 06:00
PMCR- 2021/02/17
CRDT- 2021/02/18 05:44
PHST- 2021/02/18 05:44 [entrez]
PHST- 2021/02/19 06:00 [pubmed]
PHST- 2021/11/05 06:00 [medline]
PHST- 2021/02/17 00:00 [pmc-release]
AID - 1887628 [pii]
AID - 10.1080/19420862.2021.1887628 [doi]
PST - ppublish
SO  - MAbs. 2021 Jan-Dec;13(1):1887628. doi: 10.1080/19420862.2021.1887628.