The Antibody Society

the official website of the antibody society

An international non-profit supporting antibody-related research and development.

Antibodies to watch in 2020: Will the pandemic cause delays?

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As regulatory agencies tasked with evaluating and monitoring the development of medicines, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have pivotal roles in the global response to the COVID-19 pandemic. However, these critical activities have been added to an already substantial workload. FDA and EMA are continuing the ongoing marketing application reviews for drugs that are not COVID-19 interventions, and they will need to process new applications submitted throughout 2020. FDA and EMA’s distribution of work is particularly relevant to new antibody therapeutics because a substantial number of license applications for these drugs, none of which relate to COVID-19, are undergoing FDA or EMA review. In a recent statement, FDA offered assurances that their application review teams are focused on their work, but noted that they may not be able to sustain the current level of performance indefinitely.

In total, biologics license applications (BLAs) for 14 new antibody therapeutics (i.e., not previously approved by any agency for any indication) are undergoing FDA review. EMA is reviewing marketing authorization applications (MAAs) for 4 of these 14 antibody therapeutics, and MAAs for 4 antibody therapeutics that are already approved in the US.

New antibody therapeutics undergoing FDA review

The 14 antibody therapeutics undergoing FDA review are treatments for a variety of diseases, including numerous cancers, neuromyelitis optica spectrum disorders, osteoarthritis pain, diabetes, thrombotic microangiopathies, Ebola and HIV infection. The drugs for cancer are:

  • Sacituzumab govitecan, anti-TROP-2 humanized IgG1 antibody-drug conjugate for triple-neg. breast cancer
  • Belantamab mafodotin, anti-B-cell maturation antigen humanized IgG1 antibody-drug conjugate for multiple myeloma
  • Tafasitamab, anti-CD19 humanized IgG1 for diffuse large B-cell lymphoma
  • Naxitamab, anti-GD2 humanized IgG1 for high-risk neuroblastoma and refractory osteomedullary disease
  • Oportuzumab monatox, anti-EpCAM humanized scFv immunotoxin for bladder cancer
  • Margetuximab, anti-HER2 chimeric IgG1 for HER2-positive metastatic breast cancer
  • Dostarlimab, anti-PD-1 humanized IgG4 for endometrial cancer

The drugs for non-cancer indications are:

  • Inebilizumab, anti-CD19 humanized IgG1 for neuromyelitis optica and neuromyelitis optica spectrum disorders
  • Satralizumab, anti-IL-6R humanized IgG2 for neuromyelitis optica spectrum disorders
  • Tanezumab, anti-nerve growth factor humanized IgG2 for pain due to osteoarthritis of the knee or hip
  • Teplizumab, anti-CD3 humanized IgG1 for type 1 diabetes
  • Narsoplimab, anti-MASP-2 human IgG4 for hematopoietic stem cell transplant-associated thrombotic microangiopathies
  • Leronlimab, anti-CCR5 humanized IgG4  for HIV infection
  • REGNEB3, a mixture of 3 human IgG1 targeting the Ebola virus for Ebola disease.

A first review cycle for the BLAs for all 14 should be completed by the end of 2020. Despite the pandemic, 2020 may be a record year for new antibody therapeutics approvals (potentially 17, including the 14 discussed here and the approvals for teprotumumab-trbw (Tepezza®), eptinezumab-jjmr (Vyepti®) and isatuximab-irfc (Sarclisa®) already granted in 2020, or more).

Antibody therapeutics undergoing EMA review

Like FDA, EMA is continuing to process MAAs for antibody therapeutics despite the increase in workload due to COVID-19. EMA provides monthly updates on applications for centralized marketing authorization for human medicines that they have received for evaluation. EMA’s information as of April 6, 2020, indicates that they are evaluating MAAs for 8 antibody therapeutics that, if approved, would be new to the European Union. These 8 are Belantamab mafodotin, Dostarlimab, Satralizumab and Tanezumab, which are also being reviewed by FDA, as well as:

  • Obiltoxaximab (Anthim®), anti-B. anthrasis protective antigen chimeric IgG1 approved by FDA for prevention of inhalational anthrax in 2016
  • Emapalumab (Gamifant®), anti-IFN gamma human IgG1 approved by FDA for primary hemophagocytic lymphohistiocytosis in 2018
  • Moxetumomab pasudotox (Lumoxiti®), anti-CD22 murine IgG1 dsFv immunotoxin approved by FDA for hairy cell leukemia in 2018
  • Crizanlizumab (Adakveo®) anti-P-selectin humanized IgG2 approved by FDA for sickle cell disease in 2019

Other antibodies to watch in 2020

The COVID-19 pandemic might delay the submission of marketing applications for antibody therapeutics that are now in late-stage clinical studies. As documented by Kaplon et al. in ‘Antibodies to watch in 2020’, companies developing 5 antibody therapeutics for cancer (spartalizumab, 131I-omburtamab, loncastuximab tesirine, balstilimab, and zalifrelimab) and 5 for non-cancer indications (aducanumab, evinacumab, etrolizumab, sutimlimab, and anifrolumab) had previously announced plans to submit applications to regulatory agencies during 2020. The Antibody Society will continue to monitor the development of these product candidates and report on progress. Discussion of these antibodies can be found in the ‘Antibodies to watch in 2020’ paper.

Coronavirus in the crosshairs, Part 6: Web resources

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The extraordinary scope and scale of the COVID-19 pandemic has elicited extraordinary responses world-wide. Companies, government agencies, academic institutions and non-profits located across the globe have mobilized teams to research the SARS-CoV-19 virus and COVID-19, conduct clinical studies of potential interventions that currently exist, and research and develop new interventions, including vaccines. To educate and inform, numerous organizations are also providing news and analysis of the pandemic. Importantly, much of this information has been made available free of charge. In Part 6 of our series “Coronavirus in the crosshairs“, we provide links to a sampling of websites that collectively offer extensive, and free, coverage of the COVID-19 pandemic.

Global Distribution of SARS-CoV-2

Johns Hopkins University Coronavirus Resource Center 
This website is a resource to help advance the understanding of the virus, inform the public, and brief policymakers in order to guide a response, improve care, and save lives. The site includes a global map and a map of the United States

The New York Times
This website includes analysis of recent news and maps of viral distribution.

COVID-19 Clinical Studies

A new resource for tracking COVID-19 clinical studies has been launched by Cytel. Funded in part by the Bill & Melinda Gates Foundation, the Global COVID-19 Clinical Trial Tracker is designed to identify any active interventional trials investigating treatment of COVID-19, regardless of clinical context.

Clinicaltrials.gov has one-click access to extensive information about hundreds of clinical trials associated with the key words COVID-19, SARS-CoV-2 and 2019-nCoV.

Therapeutics and Vaccines in Development

The Milken Institute has launched a COVID-19 Treatment and Vaccine Tracker. Data can be downloaded as a PDF.

BioWorld is offering a list of biopharma products in development for COVID-19, including both therapeutics and vaccines.

Regulatory Affairs Professionals Society is maintaining the Regulatory Focus COVID-19 Tracker, which is a resource for information on COVID-19 vaccine development that is updated weekly.

The Coalition for Epidemic Preparedness Innovations has published an overview of SARS-CoV-2 vaccines in development. As of April 8, 2020, they had identified 78 confirmed active projects, with 73 currently at exploratory or preclinical stages, and an additional 37 programs that were considered unconfirmed due to limited data available. As the authors note, the range of technology platforms being evaluated, including nucleic acid (DNA and RNA), virus-like particle, peptide, viral vector (replicating and non-replicating), recombinant protein, live attenuated virus and inactivated virus approaches, is striking.

Scientific and Medical Literature

The New England Journal of Medicine is now providing open access to a collection of articles and other resources on the COVID-19 outbreak, including clinical reports, management guidelines, and commentary.

Science has made their coronavirus-related content open access.

Next in Coronavirus in the crosshairs
In upcoming installments of “Coronavirus in the crosshairs“, we will discuss diagnostic tests and preliminary results of clinical studies of small molecule and biologic drugs used to treat COVID-19.

Coronavirus in the crosshairs, Part 5: Harnessing the human immune system

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Anti- SARS-CoV-2 antibodies produced by the human immune system are key to:

  • Serological tests, which identify past exposure;
  •  Convalescent plasma, which can be used to treat COVID-19 patients;
  •  Protection of healthy individuals, after vaccination.

In this installment of the “Coronavirus in the crosshairs” series, The Antibody Society provides updates on the status of anti-SARS-CoV-2 antibody tests, plasma-based therapeutics, and vaccines.

Serological tests

Detection of anti-SARS-CoV-2 antibodies in the blood of healthy people is critical to determining:

  • Who has previously been exposed to the virus, and may be able to resume work;
  • Who can donate plasma that may be a treatment for COVID-19 patients.

To be useful, however, serological tests must be accurate and reliable, which is typically evaluated by regulatory agencies based on data submitted to them by test developers. In response to the public health emergency caused by SARS-CoV-2 in the US, the Food and Drug Administration (FDA) issued guidance on COVID-19 diagnostic tests and initiated a virtual Town Hall Series on the immediately in effect guidance. Guidance issued February 29, 2020 describes FDA’s policy regarding laboratories immediately using tests they developed and validated while pursuing an emergency use authorization (EUA). Guidance updated March 16, 2020 describes additional policies regarding manufacturers immediately distributing tests they validated while pursuing an EUA and regarding certain serology tests.

To date, one serological test intended for use by clinical laboratories has been granted a EUA by FDA. On April 1, 2020 Cellex Inc. received an EUA for the qSARS-CoV-2 IgG/IgM Rapid Test, which is a qualitative test for the detection of IgM and IgG antibodies against SARSCoV-2 in serum and plasma blood specimens and venipuncture whole blood specimens collected from individuals suspected of COVID-19 by their healthcare provider. According to FDA’s April 7, 2020 update, over 70 test developers have notified the agency that they have serological tests available for use.

Further information about FDA’s Guidance on Coronavirus (COVID-19) Diagnostic Tests, including slides and transcripts from the virtual Town Hall Series can be found here.

Convalescent plasma

Plasma from patients who recover from infectious diseases, including SARS and Ebola, contains antibodies that can used to treat patients with the infections. Preliminary reports (Shen et al. study of 5 patients; Duan et al. study of 10 patients) suggest that plasma from COVID-19 patients who recovered, i.e., convalescent plasma, may benefit patients who are critically ill with the disease.

Early in the pandemic, numerous companies announced initiatives to develop convalescent plasma-based products, also known as hyperimmune therapies, for COVID-19. More recently, however, 6 companies (Biotest AG, Bio Products Laboratory, CSL Behring, LFB, Octapharma and Takeda Pharmaceutical Company Limited) have announced that they are collaborating to accelerate development of potential COVID-19 hyperimmune therapy. The alliance will develop one, unbranded anti-SARS-CoV-2 polyclonal hyperimmune immunoglobulin medicine with the potential to treat patients with serious complications from COVID-19.

Academic organizations and hospitals are also working together to develop convalescent plasma therapy. The National COVID-19 Convalescent Plasma Project comprises a group of physicians and scientists from 57 institutions in 46 states who self-organized to investigate the use of convalescent plasma in the current COVID-19 pandemic. The Mayo Clinic will be the lead institution providing coordinated access to investigational convalescent plasma for hospitalized patients with severe or life-threatening COVID-19, or those at high risk of progression to severe or life-threatening disease.

Regardless of the source of the material, well-controlled clinical trials must be conducted to rigorously evaluate the safety and efficacy of COVID-19 convalescent plasma. Such studies, sponsored by numerous organizations, are now on-going.
FDA’s recommendations for investigational COVID-19 convalescent plasma, including discussion of pathways for its use, can be found here.

Vaccines

Many organizations are conducting research on SARS-CoV-2 vaccines, and their efforts are yielding vaccine candidates that are now entering clinical study. For example, INOVIO Pharmaceuticals, Inc. announced that a clinical study for DNA vaccine candidate INO-4800 will begin this week. The Phase 1 open-label study (NCT04336410) will evaluate the safety, tolerability and immunogenicity of INO-4800 in healthy volunteers. Other vaccines in clinical studies include:

Additional vaccine candidates are expected to enter clinical studies in the next 3-4 months.

Substantial funding for vaccine development is being provided by non-profit organizations such as the Coalition for Epidemic Preparedness Innovations and the Bill & Melinda Gates Foundation. Extraordinary measures have been proposed to accelerate the process so that vaccines are available as quickly as possible. For example, in an interview conducted by Trevor Noah, Bill Gates stated that his Foundation could fund factories for simultaneous production of 7 vaccine candidates (at ~18min 30sec of the 22min interview).

James S. Huston – In Memoriam

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Post written by: Richard Begent, Ph.D., Emeritus Professor of Oncology, University College London

James S. Huston Jr, Ph.D., antibody engineer and founding President of The Antibody Society, died in Boston on March 25, 2020.

Jim Huston was a distinguished biophysicist and a pioneering antibody engineer; his creation of the single chain Fv (scFv) antibody was a seminal advance. These genetically encoded molecules could express the vast diversity of antibody repertoires, and could be used for specific target binding by themselves, incorporated into multifunctional molecules, attached to cell surfaces or applied in any number of formats relevant to biomedicine.

Antibodies with their multiple functions, including the capacity for specific binding to a range of targets, became practical pharmaceuticals with the advent of monoclonal antibodies as described by Köhler and Milstein in 1975. Genetic manipulation humanized the constant regions, making repeated administration feasible with widespread benefits for human health.

It was evident that the smallest target recognition moiety of antibodies, the variable region (Fv), if produced separately could be linked to many agents, conferring exquisite binding specificity. Since the VH and VL domains are separate in the native form of the Fv, they needed to be joined in a way that retained stability, the binding performance of the two components together, and appropriate flexibility.

Jim proposed doing this with one genetic construct that encoded a single-chain Fv (scFv) in which the VH and VL were joined by a flexible linker. The design issues were complex, but, consummate biophysicist that he was, he translated the requirements into a successful design for the linker. Working with colleagues at Creative Biomolecules, Massachusetts General Hospital and Harvard Medical School, an sFv reactive with digoxin was successfully produced and tested. The report (Huston et al 1988) of this work has been cited more than 2,300 times.

scFvs are readily expressed on the surface of filamentous bacteriophage and have often been the basis for naïve human antibody libraries with potential for rapid selection of desired binders from diverse libraries of many millions. This technology can be used for antibody discovery and humanization, and it has been the foundation of many successful commercial ventures. Jim’s own work included the demonstration of scFv fusion proteins and the first scFv intrabody therapy for the neurodegenerative condition, Huntington’s disease, an approach that is now being investigated in Parkinson’s disease.

The scFv format itself forms the targeting basis of T-cell recruiting agents, bispecific T-cell engagers (BiTEs), and chimeric antigen receptors (CARs), the antigen binding moiety of CAR-T cells. A number of products based on these formats are already licensed for clinical use, while several others are in development. This is an important beginning, but the potential for further applications is great because of the diversity of antibody repertoires and the robust nature of the sFv format.

Jim graduated in Chemistry from the University of Michigan and was awarded his Ph.D. for work on the Fd fragment of IgG and its domains, supervised by Professor Charles Tanford at Duke University. After postdoctoral research at Stanford and Harvard Medical Schools, he joined Creative Biomolecules in Boston in 1983 where he undertook the original work on scFvs. There followed numerous publications and patents relating to engineered antibodies and their applications.

Jim was one of the first people to see the long-term potential of antibody engineering and recognize how broad the applications could be. His lectures on this topic gave a unique experience in that one sometimes seemed to be discovering the meaning of his data simultaneously with him. Those who had the privilege of working with him benefited greatly not only from his generosity, enthusiasm, intellectual rigor and encouragement, but also from his ability to advise wisely or find the appropriate expert. He took the mission of advancing antibody engineering to an international level by serving as the scientific adviser to the Antibody Engineering & Therapeutics meetings for nearly 30 years. Over time, he brought the antibody engineering and therapeutics community together at meetings in San Diego and elsewhere. His insistence that scientific quality and education were the principal criteria for the program resulted in progressive growth and helped to cement a culture encompassing academia and industry. Building on this, he co-founded The Antibody Society in 2007 and was the Founding President and Chairman, remaining a Board Member until his death. He shared the gratification of many that, after a long gestation, antibody engineering is proving so beneficial to human health, with the promise of much more to come.

Jim’s many friends around the world will remember his love of life based on a deep Episcopalian faith, his pride and joy in his family, and the fortitude with which he bore illness over recent years.

The Antibody Society will honor Jim Huston and his many contributions to the field of antibody engineering at our next annual meeting.

Coronavirus in the crosshairs, Part 4: Antibody therapeutics

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The Antibody Society’s series “Coronavirus in the crosshairs” examines the ongoing discovery and development of COVID-19 interventions for broad use, including small molecule and biologic drugs, and vaccines. Parts 1 and 2 examined re-purposed small molecule and biologic drugs and new vaccines, respectively, while Part 3 focused on COVID-19 convalescent plasma treatments in development. The specific content of the posts is prioritized based on when the interventions might be available to either patients or healthy people, including health care workers. Re-purposed small molecule and biologic drugs are likely to be available first, followed by new vaccines and drugs.

In Part 4 of the series, we provide additional details about re-purposed biologics, such as monoclonal antibodies (mAbs) that are marketed or in clinical studies for other indications, that might ameliorate COVID-19 symptoms and that are already in clinicals studies of COVID-19 patients. We also discuss anti-SARS-CoV-2 antibodies that are in preclinical development and may enter clinical study by the end of 2020.

As mentioned in Part 3, there is no current evidence from randomized controlled trials to recommend any specific anti-SARS-CoV-2 treatment for patients with suspected or confirmed SARS-CoV-2 infection. Therefore, clinical studies must be done to determine the safety and efficacy of the agents when administered to COVID-19 patients.

Re-purposed mAbs in clinical studies

To date, nearly 100 mAb therapeutics are approved and currently marketed in at least one country. A number of these products have mechanisms of action that are relevant to COVID-19, although they are not anti- SARS-CoV-2 agents. Zhou et al. have shown that SARS-CoV-2 infection leads to activation of CD4+ T lymphocytes, which become pathogenic T helper (Th) 1 cells and generate cytokines such as Granulocyte-macrophage colony-stimulating factor, GM-CSF. This environment induces CD14+CD16+ monocytes with high expression of IL-6, which accelerates inflammation. Moreover, Chen et al. reported that IL-6 levels were significantly elevated in critically ill COVID-19 patients, and the extremely high IL-6 level was closely correlated with the incidence of RNAemia. Taken together, these results suggest that mAbs targeting interleukin 6 receptor (IL-6R), IL-6 or GM-CSF, may potentially limit SARS-CoV-2-related immunopathology, and thereby provide more time for anti-viral agents to work.

Anti-IL-6R mAbs tocilizumab (Actemra®) and sarilumab (Kevara®).

Tocilizumab was first approved in Japan in 2005, and it is currently marketed for rheumatoid arthritis in adults, juvenile rheumatoid arthritis, as well as treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome (CRS) in patients two years of age and older. Since severe or life-threatening cytokine release is part of the pathology of COVID-19, tocilizumab may help ameliorate symptoms of the disease. As listed on clinicaltrials.gov on March 27, 2020, 3 clinical studies of tocilizumab are recruiting COVID-19 patients and 2 additional studies are not yet recruiting patients:

  • Started on February 20, 2020, NCT04306705 is a retrospective study evaluating safety and efficacy of tocilizumab compared to continuous renal replacement therapy in controlling CRS triggered by COVID-19. The study site is Tongji Hospital, Wuhan, Hubei, China. The estimated enrollment is 120 patients and the estimated primary completion date is May 30, 2020.
  • Started on March 8, 2020, NCT04310228 is multicenter, randomized and controlled clinical trial evaluating favipiravir combined with tocilizumab in the treatment of COVID-19. The study sites are in China. The estimated enrollment is 150 patients and the estimated primary completion date is in May 2020.
  • Started on March 19, 2020, NCT04317092 is a Phase 2 study of tocilizumab in COVID-19 pneumonia. The study sites are in Italy. The estimated enrollment is 330 patients and the estimated primary completion date is in December 2020.
  • Due to start in March, NCT04315480 is a Phase 2 study of tocilizumab (RoActemra) as early treatment of patients affected by SARS-CoV2 infection with severe multifocal interstitial pneumonia. Patients will receive a single intravenous administration of 8 mg/kg tocilizumab. The study site is in Italy. The estimated enrollment is 30 patients and the estimated primary completion date is April 2020.
  • Due to start on April 3, 2020, NCT04320615 is a Phase 3 study randomized, double-blind, placebo-controlled, multicenter study to evaluate the safety and efficacy of tocilizumab in patients with severe COVID-19 pneumonia. The study sites are not yet listed. The estimated enrollment is 330 patients and the estimated primary completion date is August 31, 2021.

Sarilumab was first approved in the US in 2017, and it is currently marketed for rheumatoid arthritis in adults. As of March 27, 2020, one clinical trial of sarilumab in COVID-19 that is recruiting patients is listed on clinicaltrials.gov and 2 studies are listed as not yet recruiting:

  • Started on March 16, 2020, the Phase 2/3 NCT04315298 study is evaluating the efficacy and safety of sarilumab in hospitalized patients with COVID-19. The study site is in New York City. The estimated enrollment is 400 patients and the estimated primary completion date is March 2021.
  • Due to start in March 2020, the NCT04321993 Phase 2 study will evaluate sarilumab or small molecules as treatment of moderate to severe COVID-19 in hospitalized patients. The study includes 4 arms: 1) Lopinavir/ritonavir; 2) Hydroxychloroquine sulfate; 3) Baricitinib; and 4) Sarilumab (200 mg subcutaneous injection once). The study sites are not yet listed; the study sponsors are based in Canada. The estimated enrollment is 1000 patients and the estimated primary completion date is February 2021.
  • Due to start March 26, 2020, the Phase 2/3 NCT04324073 study will assess an intravenous dose of 400 mg of sarilumab in a 1 hour-infusion vs the best standard of care. The study site is in Paris, France. The estimated enrollment is 180 patients and the estimated primary completion date is March 2021.

In addition, tocilizumab and sarilumab will be tested head-to-head in a Phase 2 study in COVID-19 patients that is not yet recruiting.

  • Due to start on March 25, 2020, NCT04322773 is a an open-label, multicenter sequential and cluster randomized Phase 2 study of the effectiveness of interleukin-6 receptor inhibitors in the management of patients with severe SARS-CoV-2 pneumonia. The study has 3 arms: 1) single dose treatment with tocilizumab 400 mg intravenously; 2) single dose treatment with tocilizumab 2 x 162 mg subcutaneously; and 3) single dose treatment with sarilumab 1 x 200 mg subcutaneously. The study site is in Copenhagen, Denmark. The estimated enrollment is 200 patients and the estimated primary completion date is June 1, 2021.

Anti-IL-6 siltuximab (SYLVANT®)

Siltuximab was first approved in the US in 2014, and it is currently marketed for treatment of patients with multicentric Castleman’s disease. As of March 27, 2020, one clinical trial of siltuximab in COVID-19 is listed on clinicaltrials.gov:

Started on March 19, 2020, NCT04322188 is an observational case-control study of the use of siltuximab in patients diagnosed with COVID-19 infection who have developed serious respiratory complications. Patients in Cohort A and Cohort B are treated with siltuximab in a non-ICU and ICU setting, respectively. Each patient will have a matched control receiving standard treatment without siltuximab. The study site is in Italy. The estimated enrollment is 50 patients and the estimated primary completion date is May 19, 2020.

Anti-GM-CSF mAbs

No anti-GM-CSF mAbs have been approved, but 7 investigational mAbs with potentially relevant mechanisms of action are in clinical studies. Five target GM-CSF (TJ003234, Gimsilumab, Lenzilumab, Otilimab and Namilumab), 1 targets the GM-CSF receptor (Mavrilimumab) and 1 targets beta common receptor for GM-CSF, IL-3, IL-5 (CSL311). To date, companies developing TJ003234, Gimsilumab, and Lenzilumab have indicated that they plan on starting clinical studies of COVID-19 patients.

  • On March 13, 2020, I-Mab Biopharma announced that it is initiating the development of TJM2 (TJ003234) to treat cytokine storm associated with severe and critical illness caused by COVID-19. Discovered by I-Mab, TJM2’s development will start following the FDA’s acceptance of I-Mab’s Investigational New Drug application. Study sites will initially be in the US, with possible expansion into other hardest-hit countries. TJM2 was previously evaluated in a Phase 1 study of healthy adults.
  • On March 18, 2020, Roivant Sciences announced that it has engaged with regulators in the United States, Europe, and Asia to rapidly advance the clinical development of gimsilumab for the treatment of acute respiratory distress syndrome associated with SARS-CoV-2 infection. Gimsilumab has been tested two clinical studies, including a 4-week Phase 1 study of a subcutaneous formulation in healthy volunteers.
  • On March 27, 2020, Humanigen, Inc., announced that the company has submitted an initial protocol synopsis to the FDA in support of the company’s plans to initiate a multi-center, US, Phase 3 study in COVID-19 patients. Humanigen has already conducted two Phase 1 and two Phase 2 studies, including in patients with severe respiratory conditions.

Novel anti-SARS-CoV-2 antibodies in preclinical development

Numerous organizations and groups have announced plans or progress in developing anti-SARS-CoV-2 antibody therapeutics. The race will go to the swift, in this case organizations that are:

  • Already experienced in anti-infective antibody discovery;
  • Adept at antibody design, engineering and selection;
  • Able to manufacture antibodies; and
  • Experienced in regulatory affairs.

If any of these elements are missing, then the organization must be able to quickly contract the work or engage a collaborator or partner with the missing expertise.

It must be noted, however, that a single product is unlikely to meet the currently very substantial medical need, and not all product candidates will be successful in clinical studies. Therefore, many initiatives aimed at developing investigational antibodies are needed.

The development of anti-SARS-CoV-2 antibody therapeutics involves the following major steps:

  • Initiation of the discovery process using, e.g., transgenic mouse, display technology or human B cell from COVID-19 patient;
  • Identification and characterization of suitable antibodies via in vitro methods;
  • Non-clinical assessment via in vivo methods;
  • Manufacturing of material suitable for administration to humans;
  • Demonstration of safety and efficacy in humans.

Due to the severity of the pandemic, the pace of the process, which typically is quite slow, has been substantially accelerated.

As of March 27, 2020, early progress on multiple anti-SARS-CoV-2 antibody discovery programs had already been announced. For example:

  • Shanghai Junshi Biosciences Ltd. and the Institute of Microbiology of the Chinese Academy of Sciences are developing neutralizing antibodies derived from patients who recovered from COVID-19 as a potential treatment for COVID-19. The program will progress to clinical trials soon. According to a March 24, 2020 announcement, they have obtained neutralizing antibodies that can effectively block viral invasion in laboratory assays, conducted animal experiments, and are now verifying the preclinical toxicology and in vivo activity of the antibodies. An investigational new drug application, needed to initiate clinical studies, is in preparation.
  • Mabpharm Limited has generated a mAb-based fusion protein (CMAB020, STI-4920, ACE-MAB) that binds to the spike protein of the SARS-CoV-2 virus. Designed as a bispecific molecule, ACE-MAB has two functional arms: 1) a human antibody that targets the spike protein of SARS-CoV-2 with high affinity and 2) a truncated ACE2 protein that binds to a different epitope of the spike protein. ACE-MAB is in the cGMP cell line development stage by Mabpharm Limited, and could be ready for large-scale production for human clinical trials and commercialization upon receipt of requisite regulatory approvals. Mabpharma and Sorrento Therapeutics, Inc. have partnered in the development of ACE-MAB.
  • Vir Biotechnology, Inc., working with partners Xencor, Biogen and WuXi, has identified multiple human monoclonal antibody (mAb) development candidates that neutralize SARS-CoV-2. Two candidates will progress into human testing as soon as possible, with Phase 1/2 clinical testing planned for summer 2020.
  • Regeneron Pharmaceuticals has isolated virus-neutralizing, human antibodies from transgenic VelocImmune® mice, and antibodies from COVID-19 patients. From this large pool of candidates, Regeneron will select the top two antibodies for a ‘cocktail’ treatment based on potency and binding ability to the SARS-CoV-2 spike protein, as well as other desirable qualities. Regeneron aims to have an anti-SARS-CoV-2 antibody treatment ready for human testing by early summer.
  • James Crowe, MD, director of the Vanderbilt Vaccine Center announced that Vanderbilt University Medical Center, in collaboration with academic, governmental and corporate partners already have discovered SARS-CoV-2 antibodies. The collaborators aim to have antibodies for human clinical trials by summer 2020.
  • Distributed Bio has identified thousands of anti-SARS-CoV-19 antibodies, and their scientists are currently working on  engineering, selection, screening and production of candidates.
  • Specifica has used its Generation 3 platform to select hundreds of antibodies against the SARS-CoV-2 spike protein, which are undergoing testing for neutralization.
  • YUMAB has identified antibodies that were proven to inhibit infection and lyse of live cells, and plans to initiate clinical studies after regulatory permission has been granted.
  • AbCellera has identified over 500 unique human antibody sequences derived from the immune cells of COVID-19 patients. AbCellera and Eli Lilly and Company have partnered to co-develop antibody products for the treatment and prevention of COVID-19.
  • Celltrion has identified a library of antibodies sourced from the blood of recovered COVID-19 patients in Korea. These antibodies are undergoing further screening to identify those that are most effective in neutralizing SARS-CoV-2. Selected candidates will form the basis of anti-viral treatment to be tested in preclinical and clinical trials in the third quarter of 2020. Celltrion also plans to develop a ‘super antibody’ that can attach and neutralize all kinds of coronavirus-related strains, enabling further protection against unforeseen or unexpected mutations.
  • Utrecht University, Erasmus Medical Center and Harbor BioMed have developed a human antibody, 47D11, that targets the a conserved epitope on the viral spike receptor binding domain and can inhibit SARS-CoV-2. Data show that 47D11 neutralizes SARS-CoV and SARS-CoV-2 through a yet unknown mechanism that is different from receptor binding interference.
  • The lab of Xavier Saelens (VIB-UGent Center for Medical Biotechnology), in cooperation with the labs of Jason McLellan (University of Texas at Austin, US) and Markus Hoffmann and Stefan Pöhlmann (German Primate Center – Leibniz Institute for Primate Research, Göttingen, Germany) have discovered a unique antibody that is capable of binding SARS-CoV-2 and neutralizing a lab variant of the virus.

Other groups are also working on discovery initiatives. For example, the international research Corona Antibody Team, which includes the Technical University Braunschweig and European colleagues, is developing antibody-based therapies that target SARS-CoV-2. Details about additional biopharmaceutical product candidates in development for COVID-19 may be found here.

The Antibody Society will continue to monitor anti-SARS-CoV-2 antibody development, and report on progress with these and other COVID-19 interventions in the next installment of “Conronavirus in the crosshairs”.

Photo by Fusion Medical Animation on Unsplash