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1.
MAbs ; 13(1): 1887628, 2021.
Article in English | MEDLINE | ID: mdl-33596779

ABSTRACT

ABT-736 is a humanized monoclonal antibody generated to target a specific conformation of the amyloid-beta (Aß) 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 Aß 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 Aß 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.


Subject(s)
Alzheimer Vaccines/immunology , Amyloid beta-Peptides/antagonists & inhibitors , Antibodies, Monoclonal, Humanized/toxicity , Blood Platelets/drug effects , Immunity, Heterologous , Platelet Factor 4/antagonists & inhibitors , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Alzheimer Vaccines/pharmacokinetics , Alzheimer Vaccines/toxicity , Amyloid beta-Peptides/immunology , Animals , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antibody Specificity , Blood Platelets/immunology , Blood Platelets/metabolism , Female , Humans , Macaca fascicularis , Male , Mice, Inbred BALB C , No-Observed-Adverse-Effect Level , Platelet Activation/drug effects , Platelet Factor 4/immunology , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombocytopenic, Idiopathic/immunology , Risk Assessment , Time Factors , Toxicity Tests, Acute , Toxicity Tests, Chronic
2.
J Am Soc Nephrol ; 28(12): 3616-3626, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28827403

ABSTRACT

Targeted delivery of a therapeutic agent to a site of pathology to ameliorate disease while limiting exposure at undesired tissues is an aspirational treatment scenario. Targeting diseased kidneys for pharmacologic treatment has had limited success. We designed an approach to target an extracellular matrix protein, the fibronectin extra domain A isoform (FnEDA), which is relatively restricted in distribution to sites of tissue injury. In a mouse unilateral ureteral obstruction (UUO) model of renal fibrosis, injury induced significant upregulation of FnEDA in the obstructed kidney. Using dual variable domain Ig (DVD-Ig) technology, we constructed a molecule with a moiety to target FnEDA and a second moiety to neutralize TGF-ß After systemic injection of the bispecific TGF-ß + FnEDA DVD-Ig or an FnEDA mAb, chemiluminescent detection and imaging with whole-body single-photon emission computed tomography (SPECT) revealed significantly higher levels of each molecule in the obstructed kidney than in the nonobstructed kidney, the ipsilateral kidney of sham animals, and other tissues. In comparison, a systemically administered TGF-ß mAb accumulated at lower concentrations in the obstructed kidney and exhibited a more diffuse whole-body distribution. Systemic administration of the bispecific DVD-Ig or the TGF-ß mAb (1-10 mg/kg) but not the FnEDA mAb attenuated the injury-induced collagen deposition detected by immunohistochemistry and elevation in Col1a1, FnEDA, and TIMP1 mRNA expression in the obstructed kidney. Overall, systemic delivery of a bispecific molecule targeting an extracellular matrix protein and delivering a TGF-ß mAb resulted in a relatively focal uptake in the fibrotic kidney and reduced renal fibrosis.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Kidney Diseases/drug therapy , Kidney/drug effects , Transforming Growth Factor beta/antagonists & inhibitors , Animals , Disease Models, Animal , Extracellular Matrix/metabolism , Fibronectins/chemistry , Fibrosis/drug therapy , Humans , Hybridomas/metabolism , Kidney/diagnostic imaging , Kidney/pathology , Male , Mice , Tomography, Emission-Computed, Single-Photon , Ureter/pathology
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