Abstract A059: Efficacy of anti-ICOS agonist monoclonal antibodies in preclinical tumor models provides a rationale for clinical development as cancer immunotherapeutics

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.

Download Full-text

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

Download Full-text

Antiangiogenic antibody BD0801 combined with immune checkpoint inhibitors achieves synergistic antitumor activity and affects the tumor microenvironment

BMC Cancer ◽

10.1186/s12885-021-08859-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Liting Xue ◽

Xingyuan Gao ◽

Haoyu Zhang ◽

Jianxing Tang ◽

Qian Wang ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Antitumor Activity ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Clinical Development ◽

Cell Mediated Immunity ◽

Tumor Models ◽

Anti Vegf

Abstract Background Signaling through VEGF/VEGFR induces cancer angiogenesis and affects immune cells. An increasing number of studies have recently focused on combining anti-VEGF/VEGFR agents and immune checkpoint inhibitors (ICIs) to treat cancer in preclinical and clinical settings. BD0801 is a humanized rabbit anti-VEGF monoclonal antibody in the clinical development stage. Methods In this study, the anti-cancer activities of BD0801 and its potential synergistic anti-tumor effects when combined with different immunotherapies were assessed by using in vitro assays and in vivo tumor models. Ex vivo studies were conducted to reveal the possible mechanisms of actions (MOA) underlying the tumor microenvironment modification. Results BD0801 showed more potent antitumor activity than bevacizumab, reflected by stronger blockade of VEGF/VEGFR binding and enhanced inhibitory effects on human umbilical vein endothelial cells (HUVECs). BD0801 exhibited dose-dependent tumor growth inhibitory activities in xenograft and murine syngeneic tumor models. Notably, combining BD0801 with either anti-PD-1 or anti-PD-L1 antibodies showed synergistic antitumor efficacy in both lung and colorectal cancer mouse models. Furthermore, the mechanistic studies suggested that the MOA of the antitumor synergy involves improved tumor vasculature normalization and enhanced T-cell mediated immunity, including increased tumor infiltration of CD8+ and CD4+ T cells and reduced double-positive CD8+PD-1+ T cells. Conclusions These data provide a solid rationale for combining antiangiogenic agents with immunotherapy for cancer treatment and support further clinical development of BD0801 in combination with ICIs.

Download Full-text

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text