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Optimization of anti-ADAMTS13 antibodies for the treatment of ADAMTS13-related bleeding disorder in patients receiving circulatory assist device support.

ABSTRACT: ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type-1 motif 13)-related bleeding disorder has been frequently observed as a life-threatening clinical complication in patients carrying a circulatory assist device. Currently, treatment modalities for the bleeding disorder are very limited and not always successful. To address the unmet medical need, we constructed humanized antibodies of mouse anti-ADAMTS13 antibody A10 (mA10) by using complementarity-determining region (CDR) grafting techniques with human antibody frameworks, 8A7 and 16E8. The characteristics of the two humanized A10 antibodies, namely A10/8A7 and A10/16E8, were assessed in vitro and in silico. Among the two humanized A10 antibodies, the binding affinity of A10/16E8 to ADAMTS13 was comparable to that of mA10 and human-mouse chimeric A10. In addition, A10/16E8 largely inhibited the ADAMTS13 activity in vitro. The results indicated that A10/16E8 retained the binding affinity and inhibitory activity of mA10. To compare the antibody structures, we performed antibody structure modeling and structural similarity analysis in silico. As a result, A10/16E8 showed higher structural similarity to mA10, compared with A10/8A7, suggesting that A10/16E8 retains a native structure of mA10 as well as its antigen binding affinity and activity. A10/16E8 has great potential as a therapeutic agent for ADAMTS13-related bleeding disorder.

SUBMITTER: Ito T

PROVIDER: S-EPMC8595387 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Optimization of anti-ADAMTS13 antibodies for the treatment of ADAMTS13-related bleeding disorder in patients receiving circulatory assist device support.

Ito Toshihiro T Minamitani Takeharu T Hayakawa Masaki M Otsubo Ryota R Akiba Hiroki H Tsumoto Kouhei K Matsumoto Masanori M Yasui Teruhito T

Scientific reports 20211116 1

ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type-1 motif 13)-related bleeding disorder has been frequently observed as a life-threatening clinical complication in patients carrying a circulatory assist device. Currently, treatment modalities for the bleeding disorder are very limited and not always successful. To address the unmet medical need, we constructed humanized antibodies of mouse anti-ADAMTS13 antibody A10 (mA10) by using complementarity-determining region (CD ...[more]

PMID: 34785706

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Project description:BackgroundAn optimal blood pressure (BP) range to mitigate morbidity and mortality on left ventricular assist device (LVAD) support has not been clearly defined.MethodsAverage Doppler opening pressure, mean arterial pressure (MAP), and/or systolic blood pressure (SBP) were calculated in operative survivors (n = 16,155) of LVAD support in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). BP distributions were used to group patients into low (BP <25th percentile), normal (25-75th percentile), high (75th-95th percentile), and very high (>95th percentile). Associations between BP and adverse events were evaluated using Cox regression (hazard ratio[HR], 95% confidence interval).ResultsThe median (25th, 75th) MAP, Doppler, and SBP (mm Hg) during continuous flow LVAD support were 84 (77, 90), 85 (80, 92), and 99 (90, 107) mm Hg, respectively. BP had a bimodal risk association with survival. At 3 years, survival was 58% ± 1.8% in those with low MAP (≤75 mm Hg) vs 70% ± 0.9%, 71% ± 1.5%, and 63% ± 3.0% in the those with normal, high, or very high average MAP, respectively. Patients with chronically low MAP (≤75 mm Hg), Doppler (≤80 mm Hg), and SBP (<90 mm Hg) had 35%-42% higher adjusted hazards of death than patients with normal or high BP (p ≤ 0.0001). Patients with MAP >100 mm Hg, Doppler ≥105 mm Hg, and SBP ≥120 mm Hg had 17%-20% higher adjusted hazards of death than those with normal pressures (p < 0.05). In patients on axial flow LVADs, elevated SBP (HR 1.08 [95% confidence interval, 1.04-1.13] per 10 mm Hg increase) but not MAP correlated with increased incident of stroke.ConclusionsIn INTERMACS, BP extremes during LVAD support increase the risk for adverse events, supporting a MAP goal >75 mm Hg and <90 mm Hg. Hypotension conferred the highest risk for mortality. Excessive BP control should be avoided, and Doppler opening pressure should not be assumed to represent MAP in all patients.

Project description:BackgroundTime course and predictors of myocardial recovery on contemporary left ventricular assist device support are poorly defined because of limited number of recovery patients at any implanting center. This study sought to investigate myocardial recovery using multicenter data from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS).Methods and resultsThirteen thousand four hundred fifty-four adult patients were studied. Device explant rates for myocardial recovery were 0.9% at 1-year, 1.9% at 2-year, and 3.1% at 3-year follow-up. Independent predictors of device explantation for recovery were age <50 years (odds ratio [OR] 2.5), nonischemic etiology (OR 5.4), time since initial diagnosis <2 years (OR 3.4), suboptimal heart failure therapy before implant (OR 2.2), left ventricular end-diastolic diameter <6.5 cm (OR 1.7), pulmonary systolic artery pressure <50 mm Hg (OR 2.0), blood urea nitrogen <30 mg/dL (OR 3.3), and axial-flow device (OR 7.6). Patients with myocarditis (7.7%), postpartum cardiomyopathy (4.4%), and adriamycin-induced cardiomyopathy (4.1%) had highest rates of device explantation for recovery. Use of neurohormonal blockers on left ventricular assist device support was significantly higher in patients who were explanted for recovery. Importantly, 9% of all left ventricular assist device patients who were not explanted for recovery have demonstrated substantial improvement in left ventricular ejection fraction (partial recovery) and had remarkable overlap in clinical characteristic profile compared with patients who were explanted for recovery (complete recovery). Complete and partial recovery rates have declined in parallel with recent changes observed in device indications and technology.ConclusionsMyocardial recovery is a spectrum of improvement rather than a binary clinical end point. One in every 10 left ventricular assist device patients demonstrates partial or complete myocardial recovery and should be targeted for functional assessment and optimization.

Dataset Information

Optimization of anti-ADAMTS13 antibodies for the treatment of ADAMTS13-related bleeding disorder in patients receiving circulatory assist device support.

Publications

Optimization of anti-ADAMTS13 antibodies for the treatment of ADAMTS13-related bleeding disorder in patients receiving circulatory assist device support.

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