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Coronavirus in the crosshairs, Part 1

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Coronaviruses (CoVs) are enveloped positive-sense single-stranded RNA viruses that can cause highly lethal respiratory disease in humans, such as Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). The current coronavirus disease (COVID-19) pandemic is caused by the SARS-CoV-2 coronavirus. Infection in humans is initiated through exposure of the respiratory tract to the virus, which enters cells by binding angiotensin-converting enzyme 2 (ACE2) found on the cell surface.[1] Wrapp et al.[2] have shown that the SARS-CoV-2 spike protein binds to ACE2 with ~10- to 20-fold higher affinity than the spike protein of SARS–CoV, which is a coronavirus that caused an epidemic in 2002-2003.

An urgent and immediate need for knowledge about COVID-19 and for drugs to inhibit the virus and treat symptoms has existed since the disease started to spread in December 2019. To address this need, medical professionals have initiated numerous trials to identify key characteristics of the infections and the effects of investigational and approved drugs, including those used during the MERS and SARS outbreaks. As of March 19, 2020, clinicaltrials.gov already included ~115 studies related to COVID-19, with ~40 designed as observational studies or studies of diagnostics or devices, and ~75 designed to evaluate interventions such as antiviral drugs. Of the interventional studies, ~40 are currently recruiting patients, and the rest have not yet started recruiting. The earliest of these studies were started in China in late January 2020; additional studies may be listed on the Chinese clinical trials registry. Many studies are designed to produce results rapidly, which may greatly assist treatment of patients in the near future.

Effective in vitro inhibition of SARS-CoV-2 by remdesivir and chloroquine has been reported,[3] and numerous clinical studies are underway to determine the efficacy of these drugs as COVID-19 treatments.[4] Remdesivir (GS-5734, Gilead Sciences Inc) is an investigational monophosphoramidate prodrug of an adenosine analog with potent activity against an array of RNA virus families, including Filoviridae, Paramyxoviridae, Pneumoviridae, and Orthocoronavirinae, through the targeting of the viral RNA-dependent RNA polymerase. It was previously tested in humans with Ebola virus disease, and has demonstrated positive results in animal models of MERS.[5] Numerous clinical studies of the effects are remdesivir are ongoing, including:

  • NCT04257656, started February 6, 2020 in China, with estimated enrollment of 453 patients and a primary completion date of April 3, 2020.
  • NCT04252664, started February 12, 2020 in China, with estimated enrollment of 308 patients and a primary completion date of April 20, 2020.
  • NCT04280705, started February 21, 2020 in the US, South Kora and Singapore, with estimated enrollment of 394 patients and a primary completion date of April 1, 2020.[6]
  • NCT04292899, started March 6, 2020 in the US, South Kora and Singapore, with estimated enrollment of 400 patients and a primary completion date of May 2020.
  • NCT04292730, started on March 15, 2020 in the US, South Kora and Singapore, with estimated enrollment of 600 patients and a primary completion date of May 2020.

The U.S. Army Medical Research and Development Command is sponsoring a study of remdesivir (NCT04302766) with enrollment limited to DoD-affiliated personnel (including active and reserve component service members, US civilian employees, contractors, other US personnel, and dependents of any age, as well as allied military forces and local nationals) who have a COVID-19 diagnosis and have been granted access to the medical facility.

Hydroxychloroquine, which is FDA-approved as a treatment for malaria, lupus and rheumatoid arthritis, appears to interfere with terminal glycosylation of ACE2 and is known to elevate endosomal pH, which may inhibit virus binding and subsequent infection.[7] Preliminary evidence from a small study in humans suggests that the combination of azithromycin and hydroxychloroquine is significantly more efficient for virus elimination.[8] 

At least 3 clinical studies of the effects are hydroxychloroquine are ongoing:

  • NCT04261517, started February 6, 2020 in Shanghai, with estimated enrollment of 30 patients and a primary completion date of August 2020.
  • NCT04307693, started March 11, 2020 in Seoul, South Korea, with estimated enrollment of 150 patients and a primary completion date of May 2020.
  • NCT04308668, started March 2020 in Minneapolis, Minnesota, United States, with estimated enrollment of 1500 patients and a primary completion date of May 2021.

On March 18, 2020, the World Health Organization announced that they are planning a multi-arm clinical trial that will evaluate the following drugs as treatments for COVID-19:

  • Remdesivir;
  • Hydroxychloroquine or chloroquine;
  • Lopinavir-ritonavir (a combination of two HIV drugs marketed as Kaletra or Aluvia); and
  • Lopinavir-ritonavir plus interferon beta.

Argentina, Bahrain, Canada, France, Iran, Norway, South Africa, Spain, Switzerland, and Thailand have offered study sites, and sites in other countries may be added in the future. The study, called SOLIDARITY, will use an adaptive design, which allows study arms to be modified, added or eliminated based on the results of ongoing data collection.[9] The lopinavir-ritonavir arms are included in the SOLIDARITY study despite the negative results of a clinical study of 199 hospitalized adult patients with severe COVID-19 in China, which showed no benefit from adding lopinavir–ritonavir treatment to standard care.[10] Further study is needed to understand whether factors such as the drug dose or patient characteristics (age, severity of disease, underlying medical conditions) affected the possibility of a treatment benefit.

In addition, positive results have been reported for the antiviral agent favipiravir (Avigan), which was evaluated in COVID-19 patients in clinical trials conducted in Wuhan and Shenzhen, China. Favipiravir was approved in 2014 in Japan for treatment of influenza, although use is limited because the drug may cause fetal deaths or deformities. Additional studies in COVID-19 are needed, however, results reported by Japanese health officials suggest the drug is less effective in patients with more severe symptoms.[11]

Other antiviral treatments are currently being evaluated, including anti-SARS-CoV-2 inactivated convalescent plasma (NCT04292340), as are therapies that can ameliorate symptoms of the disease, including anti-IL-6 sarilumab (NCT04315298) and anti-IL-6 receptor tocilizumab (NCT04306705, NCT04310228), which may reduce lung inflammation and improve lung function in COVID-19 patients.

Scientists are searching for new treatments and vaccines, which will be discussed in our upcoming posts.

1. Walls et al. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. March 09, 2020. DOI:https://doi.org/10.1016/j.cell.2020.02.058
2. Wrapp et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020, 367, 1260-1263.
3. Wang et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 2020, 30, 269–271.
4. Food and Drug Administration, March 19, 2020. Coronavirus (COVID-19) Update: FDA Continues to Facilitate Development of Treatments.
5. National Institutes of Health, February 13, 2020. Remdesivir Prevents MERS Coronavirus Disease in Monkeys.
6. National Institutes of Health, February 25, 2020. NIH clinical trial of remdesivir to treat COVID-19 begins.
7. Vincent et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virology Journal 2005, 2, 69.
8. Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of COVID‐19: results of an open‐label non‐randomized clinical trial. International Journal of  Antimicrobial Agents – In Press 17 March 2020 – DOI : 10.1016/j.ijantimicag.2020.105949
9. WHO Director-General’s opening remarks at the media briefing on COVID-19 – 18 March 2020.
10. Cao et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. New England Journal of Medicine. March 18, 2020. DOI: 10.1056/NEJMoa2001282.
11. Watanabe S, Chan M, Suzuki W. China says Japan-developed drug Avigan works against coronavirus. Nikkei Asian Review. March 18, 2020.

Coronavirus image from: CDC/ Alissa Eckert, MS; Dan Higgins, MAMS

“Antibodies to Watch in 2020” at PEGS Europe

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Over the past decade, the ‘Antibodies to Watch’ article series has documented the results of the global biopharmaceutical industry’s efforts to bring innovative antibody therapeutics to patients in need. Dr. Janice Reichert, Executive Director of The Antibody Society, offered a preview of the 2020 version on Wednesday November 20, 2019 during the ‘Developing Successful Antibody Products’ session at PEGS Europe.

‘Antibodies to watch in 2020’ includes updates on recent and anticipated events relevant to antibody therapeutics in clinical development. Data for antibody therapeutics that were first approved in either the US or EU during 2019, as well as several products first approved in Russia or India, were provided. Antibody therapeutics undergoing regulatory review by the Food and Drug Administration or the European Medicines Agency as of November 2019 were also discussed. Brief summaries of antibody therapeutics in late-stage clinical study that may progress to regulatory review in late 2019 or 2020, based on public disclosures by the sponsoring companies, were included. In concluding, Dr. Reichert noted that the late-stage clinical pipeline is robust, and she anticipated that more antibody therapeutics will be in late-stage studies in 2020 than any year previously documented. Remarkably, compared to 2010, the number of antibody therapeutics currently in late-stage studies has nearly tripled (to 75 antibody therapeutics).

The ‘Antibodies to watch in 2020′ presentation can be downloaded here.

The Antibody Society was very pleased to see so many of our corporate sponsors in attendance at PEGS Europe!

Join Us for Antibody Engineering & Therapeutics Digital Week!

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Antibody Engineering & Therapeutics Digital Week is a global 4-day series of live educational webcasts and downloadable resources providing the latest insights for accelerating next generation antibodies to commercial success.

The clinical pipeline of antibody therapeutics will be discussed in The Antibody Society’s “Antibodies to Watch” and More: Early- and Late-stage Clinical Development Trends presentation, scheduled for 11am EDT / 4pm BST / 5pm CEST Wednesday June 26, 2019.

The “Antibodies to watch” talks and papers focus on antibody therapeutics in late-stage clinical studies, as well as those is regulatory review and recently approved in the US and European Union. These topics will be discussed, along with trends observed in the burgeoning early-stage pipeline. Popular formats and mechanisms of action, as well as popular and obscure targets, for antibody therapeutics that recently entered the clinical pipeline will be included.

Click here to register for Digital Week.

Antibody therapeutics in early-stage clinical studies

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The popular “Antibodies to watch” articles aim to update members of The Antibody Society, as well as the broader scientific community, on progress in the late-stage clinical development of innovative antibody therapeutics. Data for these molecules (60 as of March 22, 2019) are made available in the Members Only area of The Antibody Society’s website. We are pleased to announce that we are expanding our coverage of the commercial clinical pipeline to include data for antibody therapeutics that have recently entered clinical study. Two factors motivated us: 1) the remarkable increase in the number entering clinical study annually (to ~120 in 2018); and 2) the remarkable focus on antibodies developed for cancer (~80% of the total in 2018). Data for antibody therapeutics that entered clinical study recently, in Excel format, may be downloaded from the Members Only area.

The biopharmaceutical industry’s intense focus on the development of antibody therapeutics, and particularly those for cancer, is unabated in 2019, according to the data available by mid-March. We have identified 17 antibody therapeutics for which an application to start clinical study was filed or a Phase 1 study was started in 2019, and an additional 11 antibody therapeutics with clinical studies not yet recruiting patients, as listed on clinicaltrials.gov. The rate of clinical entry for antibody therapeutics so far in 2019 is thus similar to that observed in 2018 (~10 per month). The trend toward development of antibodies as treatments for cancer is also quite similar. Of the 2019 cohort so far identified, 22 of 28 (79%) are for cancer.

The commercial clinical pipeline of cancer therapies has become increasingly dominated by 3 categories of antibodies: 1) immune checkpoint modulators; 2) antibody-drug conjugates (ADCs); and 3) bispecific antibodies (see figure for details).

Our data so far suggests that this trend will continue in 2019, as nearly three-quarters of the antibody therapeutics currently in the 2019 cohort fit in one (or more) of the 3 categories. Examples of antibodies that fit more than 1 category include TG-1801 (TG Therapeutics, Inc., Novimmune SA), a bispecific antibody targeting the immune checkpoint CD47 as well as CD19, and  INBRX-105 (Inhibrx, Inc.), a bispecific antibody targeting the immune checkpoints PD-L1 and 4-1BB. TG-1801, a human IgG1 designed to target and deplete B-cells, is undergoing evaluation in a Phase 1 study (NCT03804996) of patients with B-cell lymphoma. INBRX-105 is undergoing evaluation as a treatment for hematological and solid tumors in a Phase 1 study (NCT03809624).

More to come! Throughout 2019, we will track and report on the development of all antibody therapeutics that enter clinical study during the year.

Attention members! Please log in to access our data for all antibody therapeutics that entered clinical study during 2018 or so far in 2019. After logging in, click on ‘Antibodies in early-stage studies’ in the Members Only dropdown menu. Data will be updated throughout 2019.

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Most read from mAbs, Feb/March 2019

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The Antibody Society is pleased and proud to be affiliated with mAbs, a multi-disciplinary journal dedicated to advancing the art and science of antibody research and development. We hope you enjoy these summaries based on the abstracts of the most read papers published in a recent issue. All the articles are open access; PDFs can be freely downloaded by following the links below.

Issue 11.2 (February/March 2019)

Antibodies to watch in 2019.
For the past 10 years, the annual ‘Antibodies to watch’ articles have provided updates on key events in the late-stage development of antibody therapeutics, such as first regulatory review or approval, that occurred in the year before publication or were anticipated to occur during the year of publication. To commemorate the 10th anniversary of the article series and to celebrate the 2018 Nobel Prizes in Chemistry and in Physiology or Medicine, which were given for work that is highly relevant to antibody therapeutics research and development, Kaplon and Reichert expanded the scope of the data presented to include an overview of all commercial clinical development of antibody therapeutics and approval success rates for this class of molecules. The data indicate that:
1) antibody therapeutics are entering clinical study, and being approved, in record numbers;
2) the commercial pipeline is robust, with over 570 antibody therapeutics at various clinical phases, including 62 in late-stage clinical studies; and
3) Phase 1 to approval success rates are favorable, ranging from 17–25%, depending on the therapeutic area (cancer vs. non-cancer).

Ion channels as therapeutic antibody targets.
In this review, Hutchings et al evaluate the technical challenges of raising antibodies to membrane-spanning proteins together with enabling technologies that may facilitate the discovery of antibody therapeutics to ion channels. They also discuss the potential targeting opportunities in the anti-ion channel antibody landscape, along with a number of case studies where functional antibodies that target ion channels have been reported. Antibodies currently in development and progressing towards the clinic are highlighted.

Influence of N-glycosylation on effector functions and thermal stability of glycoengineered IgG1 monoclonal antibody with homogeneous glycoforms.
The separation of various glycoforms to investigate the biological and functional relevance of glycosylation is a major challenge, and the individual contributions of each glycoform is usually not considered when evaluating mAbs with highly heterogeneous distributions. In this study, Wada et al used chemoenzymatic glycoengineering incorporating an endo-β-N-acetylglucosaminidase (ENGase) EndoS2 and its mutant with transglycosylation activity to generate mAb glycoforms with highly homogeneous and well-defined N-glycans to better understand and precisely evaluate the effect of each N-glycan structure on Fc effector functions and protein stability. They demonstrated that the core fucosylation, non-reducing terminal galactosylation, sialylation, and mannosylation of IgG1 mAb N-glycans impact not only on FcγRIIIa binding, antibody-dependent cell-mediated cytotoxicity, and C1q binding, but also FcRn binding, thermal stability and propensity for protein aggregation.

Co-engaging CD47 and CD19 with a bispecific antibody abrogates B-cell receptor/CD19 association leading to impaired B-cell proliferation.
In this report, Hatterer et al describes the generation of a CD47xCD19 bispecific antibody (biAb) to target and deplete B cells via multiple antibody-mediated mechanisms. Interestingly, the biAb, constructed of a CD19 binding arm and a CD47 binding arm, inhibited BCR-mediated B-cell proliferation with an effect even more potent than a CD19 monoclonal antibody (mAb). The inhibitory effect of the biAb was not attributable to CD47 binding because a monovalent or bivalent anti-CD47 mAb had no effect on B cell proliferation. Fluorescence resonance energy transfer analysis demonstrated that co-engaging CD19 and CD47 prevented CD19 clustering and its migration to BCR clusters, while only engaging CD19 (with a mAb) showed no impact on either CD19 clustering or migration. The lack of association between CD19 and the BCR resulted in decreased phosphorylation of CD19 upon BCR activation. Furthermore, the biAb differentially modulated BCR-induced gene expression compared to a CD19 mAb. Taken together, this unexpected role of CD47xCD19 co-ligation in inhibiting B cell proliferation illuminates a novel approach in which two B cell surface molecules can be tethered, to one another in order, which may provide a therapeutic benefit in settings of autoimmunity and B cell malignancies.

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