scholarly journals Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection

2018 ◽  
Vol 118 (5) ◽  
pp. 679-697 ◽  
Author(s):  
Marie Viala ◽  
Marie Vinches ◽  
Marie Alexandre ◽  
Caroline Mollevi ◽  
Anna Durigova ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Clinical Development ◽  
Dose Selection ◽  
Human Trials

Strategies for clinical development of monoclonal antibodies beyond first-in-man trials: Tested doses and rationale for dose selection.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. 3040-3040
Author(s):  
Marie Vinches ◽  
Alice Cuenant ◽  
Marie Alexandre ◽  
Anna Durigova ◽  
Nadia Hayaoui ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Clinical Development ◽  
Dose Selection

scholarly journals Correlations for tested doses and toxicities between first-in-human trials and registration trials of FDA-approved monoclonal antibodies

2016 ◽  
Vol 27 ◽  
pp. vi128
Author(s):  
M. Viala ◽  
M. Vinches ◽  
C. Mollevi ◽  
C. Gongora ◽  
L. Gianni ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Human Trials

scholarly journals Elevated Serum Sorbitol and not Fructose in Type 2 Diabetic Patients

2010 ◽  
Vol 5 ◽  
pp. BMI.S4530 ◽  
Author(s):  
Gregory M. Preston ◽  
Roberto A. Calle
Keyword(s):  
Elevated Serum ◽  
Fold Increase ◽  
Clinical Development ◽  
Gas Chromatography Mass Spectrometry ◽  
Diabetic Patients ◽  
Dose Selection ◽  
Type 2 Diabetic Patients ◽  
Early Proof ◽  
Proof Of Mechanism

Reductions in fasting serum fructose or erythrocyte sorbitol have been proposed as markers for early proof of mechanism in clinical development of aldose reductase (AR) inhibitors. However fructose is significantly impacted by meals and evaluation of erythrocyte sorbitol poses technical challenges. To more accurately assess the performance of these markers in biological samples, a gas chromatography-mass spectrometry assay was modified and validated. Serum was collected on three consecutive days from 13 healthy volunteers (HV) and 14 patients with type 2 diabetes mellitus (T2DM), and assayed for sorbitol and fructose using this assay. Serum fructose and sorbitol were relatively constant across the three days. Fasting fructose levels were comparable between the two groups (T2DM: 1.48 ± 0.49 mg/L; HV: 1.39 ± 0.38 mg/L, mean ± standard deviation, P = 0.61), but fasting sorbitol levels were significantly higher in diabetics (T2DM: 0.280 ± 0.163 mg/L; HV: 0.164 ± 0.044 mg/L, P = 0.02). Feeding resulted in a 5–6 fold increase in serum fructose levels, but only a 5%-10% increase in sorbitol. Only sorbitol remained significantly elevated pre- and post feeding in T2DM patients relative to HV. These data suggest that serum sorbitol may be a robust proof of mechanism biomarker and facilitate dose selection for clinical development of AR inhibitors.

scholarly journals Interleukin-17 cytokines: Effectors and targets in psoriasis—A breakthrough in understanding and treatment

2019 ◽  
Vol 217 (1) ◽  
Author(s):  
Immo Prinz ◽  
Inga Sandrock ◽  
Ulrich Mrowietz
Keyword(s):  
Monoclonal Antibodies ◽  
Inflammatory Diseases ◽  
Clinical Development ◽  
Tissue Homeostasis ◽  
Central Position ◽  
Interleukin 17 ◽  
Line Treatment ◽  
First Line ◽  
Intercellular Network ◽  
First Line Treatment

The IL-17 cytokine family comprising IL-17A to IL-17F and receptor subunits IL-17RA to IL-17RE represents a genetically ancient intercellular network regulating local tissue homeostasis. Its pivotal role in antifungal defense and its central position in the pathogenesis of inflammatory diseases including psoriasis were discovered only relatively late in the early 2000s. Since the connection of dysregulated IL-17 and psoriasis pathogenesis turned out to be particularly evident, a number of monoclonal antibodies targeting IL-17 pathways have been approved and are used as first line treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis, and further agents are currently in clinical development.

scholarly journals Potent Neutralizing Antibodies Directed to Multiple Epitopes on SARS-CoV-2 Spike

2020 ◽  
Author(s):  
Lihong Liu ◽  
Pengfei Wang ◽  
Manoj S. Nair ◽  
Jian Yu ◽  
Micah Rapp ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Global Economy ◽  
Epitope Mapping ◽  
Severe Disease ◽  
Clinical Development ◽  
Receptor Binding Domain ◽  
Cryo Electron Microscopy ◽  
Novel Coronavirus

AbstractThe SARS-CoV-2 pandemic rages on with devasting consequences on human lives and the global economy1,2. The discovery and development of virus-neutralizing monoclonal antibodies could be one approach to treat or prevent infection by this novel coronavirus. Here we report the isolation of 61 SARS-CoV-2-neutralizing monoclonal antibodies from 5 infected patients hospitalized with severe disease. Among these are 19 antibodies that potently neutralized the authentic SARS-CoV-2 in vitro, 9 of which exhibited exquisite potency, with 50% virus-inhibitory concentrations of 0.7 to 9 ng/mL. Epitope mapping showed this collection of 19 antibodies to be about equally divided between those directed to the receptor-binding domain (RBD) and those to the N-terminal domain (NTD), indicating that both of these regions at the top of the viral spike are immunogenic. In addition, two other powerful neutralizing antibodies recognized quaternary epitopes that are overlapping with the domains at the top of the spike. Cryo-electron microscopy reconstructions of one antibody targeting RBD, a second targeting NTD, and a third bridging two separate RBDs revealed recognition of the closed, “all RBD-down” conformation of the spike. Several of these monoclonal antibodies are promising candidates for clinical development as potential therapeutic and/or prophylactic agents against SARS-CoV-2.

scholarly journals Guiding dose selection of monoclonal antibodies using a new parameter (AFTIR) for characterizing ligand binding systems

2019 ◽  
Vol 46 (3) ◽  
pp. 287-304 ◽  
Author(s):  
Sameed Ahmed ◽  
Miandra Ellis ◽  
Hongshan Li ◽  
Luca Pallucchini ◽  
Andrew M. Stein
Keyword(s):  
Monoclonal Antibodies ◽  
Ligand Binding ◽  
Dose Selection ◽  
Selection Of

Monoklonális ellenanyag-alapú terápia myeloma multiplexben

2021 ◽  
Vol 54 (1) ◽  
pp. 27-36
Author(s):  
Apor Hardi ◽  
András Kozma ◽  
Andrea Ceglédi ◽  
Ágnes Tomán ◽  
András Bors ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Plasma Cell ◽  
Clinical Studies ◽  
Clinical Development ◽  
Bispecific Antibodies ◽  
Advanced Stages ◽  
Therapeutic Monoclonal Antibodies ◽  
Therapeutic Settings ◽  
Cell Malignancy

Összefoglaló. A monoklonális ellenanyagokat termelő plazmasejtburjánzás, a myeloma multiplex kezelésére a monoklonális ellenanyag-terápia viszonylag későn lépett a klinikumba. 2020 végén már három törzskönyvezett antitest, az elotuzumab, a daratumumab és az isatuximab áll rendelkezésre különböző gyógyszer-kombinációk részeként a myeloma betegség eltérő terápiás helyzeteinek megoldására. Emellett számos új antitest, nemcsak „csupasz” antitestek, hanem antitestdrug konjugátumok és bispecifikus antitestek állnak viszonylag előrehaladott klinikai fejlesztési stádiumban, közvetlenül a bevezetés előtt. Összefoglalónkban a rendelkezésünkre álló nagyszámú tanulmány eredményeit ismertetjük, fogódzót kínálva a terület eredményeit kritikus szemmel megismerni kívánó olvasóknak. Summary. Although multiple myeloma is a plasma cell malignancy known to produce monoclonal antibodies, therapeutic monoclonal antibodies entered late into this clinical field. At the end of 2020, we already have three approved monoclonal antibodies: elotuzumab, daratumamab, and isatuximab – available in different drug combinations at different therapeutic settings of multiple myeloma. Additionally, there are a number of new antibodies, not just „bare” antibodies but antibody-dug conjugates and bispecific antibodies stand at advanced stages of clinical development, frequently just before approval. In this review, results of the large number of clinical studies are critically detailed in order to provide assistance for our interested readers.

Characterization of two in vivo challenge models to measure functional activity of monoclonal antibodies to Plasmodium falciparum circumsporozoite protein

2020 ◽  
Author(s):  
Rama Raghunandan ◽  
Bryan T Mayer ◽  
Yevel Flores-Garcia ◽  
Monica W Gerber ◽  
Raphael Gottardo ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Monoclonal Antibodies ◽  
Functional Activity ◽  
Statistical Power ◽  
Rank Order ◽  
Circumsporozoite Protein ◽  
Dose Selection ◽  
Selection Of

Abstract Background New strategies are needed to reduce the incidence of malaria, and promising approaches include the development of vaccines and monoclonal antibodies (mAbs) that target the circumsporozoite protein (CSP). To select the best candidates and speed development, it is essential to standardize preclinical assays to measure the potency of such interventions in animal models. Methods Two assay configurations were studied using transgenic Plasmodium berghei expressing Plasmodium falciparum full-length circumsporozoite protein. The assays measured 1) reduction in parasite infection of the liver (liver burden) following an intravenous (i.v) administration of sporozoites and 2) protection from parasitaemia following mosquito bite challenge. Two human CSP mAbs, AB311 and AB317, were compared for their ability to inhibit infection. Multiple independent experiments were conducted to define assay variability and resultant impact on the ability to discriminate differences in mAb functional activity. Results Overall, the assays produced highly consistent results in that all individual experiments showed greater functional activity for AB317 compared to AB311 as calculated by the dose required for 50% inhibition (ID50) as well as the serum concentration required for 50% inhibition (IC50). The data were then used to model experimental designs with adequate statistical power to rigorously screen, compare, and rank order novel anti-CSP mAbs. Conclusion The results indicate that in vivo assays described here can provide reliable information for comparing the functional activity of mAbs. The results also provide guidance regarding selection of the appropriate experimental design, dose selection, and group sizes.

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