Clinical development methodology for infusion-related reactions with monoclonal antibodies

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.3040 ◽

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

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

10.1101/2020.06.17.153486 ◽

2020 ◽

Cited By ~ 12

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.

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Monoklonális ellenanyag-alapú terápia myeloma multiplexben

Hematológia−Transzfuziológia ◽

10.1556/2068.2021.54.1.5 ◽

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.

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Neutralization Diversity of HIV-1 Indian Subtype C Envelopes Obtained From Cross Sectional and Followed up Individuals Against Broadly Neutralizing Monoclonal Antibodies Having Distinct Gp120 Specificities

10.21203/rs.3.rs-148517/v1 ◽

2021 ◽

Author(s):

Ranajoy Mullick ◽

Jyoti Sutar ◽

Nitin Hingankar ◽

Suprit Deshpande ◽

Madhuri Thakar ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Additive Model ◽

Clinical Development ◽

Intervention Strategies ◽

Subtype C ◽

Cross Sectional ◽

Clade C ◽

Potential Use ◽

Hiv 1 ◽

Comprehensive Study

Abstract Background. The potential use of the broadly neutralizing monoclonal antibodies (bnAbs) towards prophylaxis and treatment to HIV-1 is currently being explored. While a number of promising bnAbs have been discovered and few of them have progressed towards clinical development, their extent of neutralization coverage with respect to global HIV-1 variants given the existence of genetically distinct subtypes and recombinants circulating globally is not clearly known. In the present study, we examined the variation in the neutralization susceptibility of pseudoviruses expressing 71 full length primary HIV-1 subtype C envs obtained from limited cross-sectional individuals over different time points against four bnAbs that target gp120 with distinct specificities: VRC01, CAP256-VRC26.25, PGDM1400 and PGT121. Results. We found significant variations in the susceptibility of Indian clade C to these four bnAbs and were found to be distinct to that observed with that of African subtype C based on the existing datasets and were also found to be concordant with their sequence diversity. Trend analysis indicated an increasing neutralization resistance observed overtime with CAP25-VRC26.25, PGDM1400 and PGT121 when tested on pseudoviruses expressing envs obtained from 1999-2016. Our data was found to be distinct from what was observed in case of African HIV-1 subtype C. However, inconsistent trend in neutralization susceptibility was observed, when pseudoviruses expressing envs obtained from three followed up individuals were examined. Finally, through predictive analysis of the 98 Indian subtype C including those assessed in the present study by employing additive model implemented in CombiNAber (www.hiv.lanl.gov), we observed two possibilities where combinations of three bnAbs (VRC01/CAP56-VRC26.25/PGT121 and PGDM1400/CAP256-VRC26.25/PGT121) could achieve near 100% neutralization coverage. Conclusions. Our findings not only indicate disparate intra-clade C genetic vis-à-vis neutralization diversities but also warrants the need for more comprehensive study using additional isolates towards comparing inter and intra-clade neutralization diversities which will be necessary for selecting the bnAb combinations suitable for optimal coverage of the region-specific HIV-1 circulating subtypes. Expanding these efforts is imperative for designing efficacious bnAb based intervention strategies for India as well as subtype C in general.

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An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by several therapeutic monoclonal antibodies

10.1101/2021.12.15.472828 ◽

2021 ◽

Author(s):

Laura A VanBlargan ◽

John M Errico ◽

Peter Halfmann ◽

Seth J Zost ◽

James E. Crowe ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Severe Acute Respiratory Syndrome ◽

Clinical Development ◽

Spike Protein ◽

Clinical Use ◽

Receptor Binding Domain ◽

Antigenic Sites ◽

Recent Emergence ◽

Therapeutic Monoclonal Antibodies ◽

The Impact

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic resulting in millions of deaths worldwide. Despite the development and deployment of highly effective antibody and vaccine countermeasures, rapidly-spreading SARS-CoV-2 variants with mutations at key antigenic sites in the spike protein jeopardize their efficacy. Indeed, the recent emergence of the highly-transmissible B.1.1.529 Omicron variant is especially concerning because of the number of mutations, deletions, and insertions in the spike protein. Here, using a panel of anti-receptor binding domain (RBD) monoclonal antibodies (mAbs) corresponding to those with emergency use authorization (EUA) or in advanced clinical development by Vir Biotechnology (S309, the parent mAbs of VIR-7381), AstraZeneca (COV2-2196 and COV2-2130, the parent mAbs of AZD8895 and AZD1061), Regeneron (REGN10933 and REGN10987), Lilly (LY-CoV555 and LY-CoV016), and Celltrion (CT-P59), we report the impact on neutralization of a prevailing, infectious B.1.1.529 Omicron isolate compared to a historical WA1/2020 D614G strain. Several highly neutralizing mAbs (LY-CoV555, LY-CoV016, REGN10933, REGN10987, and CT-P59) completely lost inhibitory activity against B.1.1.529 virus in both Vero-TMPRSS2 and Vero-hACE2-TMPRSS2 cells, whereas others were reduced (~12-fold decrease, COV2-2196 and COV2-2130 combination) or minimally affected (S309). Our results suggest that several, but not all, of the antibody products in clinical use will lose efficacy against the B.1.1.529 Omicron variant and related strains.

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Case studies of monoclonal antibodies for cancer therapy: technology drives clinical development

Monoclonal Antibodies: Development, Delivery and Applications ◽

10.4155/fseb2013.13.86 ◽

2015 ◽

pp. 156-165

Author(s):

Andrew Lupo ◽

Lei Zheng

Keyword(s):

Monoclonal Antibodies ◽

Cancer Therapy ◽

Case Studies ◽

Clinical Development

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Neutralization diversity of HIV-1 Indian subtype C envelopes obtained from cross sectional and followed up individuals against broadly neutralizing monoclonal antibodies having distinct gp120 specificities

Retrovirology ◽

10.1186/s12977-021-00556-2 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Ranajoy Mullick ◽

Jyoti Sutar ◽

Nitin Hingankar ◽

Suprit Deshpande ◽

Madhuri Thakar ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Additive Model ◽

Clinical Development ◽

Intervention Strategies ◽

Subtype C ◽

Cross Sectional ◽

Clade C ◽

Potential Use ◽

Hiv 1 ◽

Comprehensive Study

Abstract Background The potential use of the broadly neutralizing monoclonal antibodies (bnAbs) towards prophylaxis and treatment to HIV-1 is currently being explored. While a number of promising bnAbs have been discovered and a few of them have progressed towards clinical development, their extent of neutralization coverage with respect to global HIV-1 variants given the existence of genetically distinct subtypes and recombinants circulating globally is not clearly known. In the present study, we examined the variation in the neutralization susceptibility of pseudoviruses expressing 71 full length primary HIV-1 subtype C envs obtained from limited cross-sectional individuals over different time points against four bnAbs that target gp120 with distinct specificities: VRC01, CAP256-VRC26.25, PGDM1400 and PGT121. Results We found significant variations in the susceptibility of Indian clade C to these four bnAbs. These variations were found to be distinct to that observed in African subtype C based on the existing datasets and concordant with their sequence diversity. Trend analysis indicated an increasing neutralization resistance observed over time with CAP25-VRC26.25, PGDM1400 and PGT121 when tested on pseudoviruses expressing envs obtained from 1999 to 2016. However, inconsistent trend in neutralization susceptibility was observed, when pseudoviruses expressing envs obtained from three followed up individuals were examined. Finally, through predictive analysis of the 98 Indian subtype C including those assessed in the present study by employing additive model implemented in CombiNAber (http://www.hiv.lanl.gov), we observed two possibilities where combinations of three bnAbs (VRC01/CAP56-VRC26.25/PGT121 and PGDM1400/CAP256-VRC26.25/PGT121) could achieve near 100% neutralization coverage. Conclusions Our findings not only indicate disparate intra-clade C genetic vis-à-vis neutralization diversities but also warrant the need for more comprehensive study using additional isolates towards comparing inter and intra-clade neutralization diversities which will be necessary for selecting the bnAb combinations suitable for optimal coverage of the region-specific HIV-1 circulating subtypes. Expanding these efforts is imperative for designing efficacious bnAb based intervention strategies for India as well as subtype C in general.

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