The Antibody Society

the official website of the antibody society

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

FDA approves sacituzumab govitecan (Trodelvy®) for triple-negative breast cancer

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On April 22, 2020, the US Food and Drug Administration (FDA) granted an accelerated approval to Trodelvy® (sacituzumab govitecan-hziy) for the treatment of patients with metastatic triple-negative breast cancer who received at least two prior treatments for metastatic disease. Sacituzumab govitecan is composed of an anti-TROP-2 humanized IgG1 antibody conjugated to the topoisomerase inhibitor SN38, which is the active metabolite of irinotecan.

The approval was based on the results of a clinical trial of 108 patients with metastatic triple-negative breast cancer who had received at least two prior treatments for metastatic disease. In this study, the overall response rate was 33.3%, with a median duration of response of 7.7 months. Of the patients who responded to treatment, 55.6% maintained their response for 6 or more months and 16.7% maintained their response for 12 or more months.

The accelerated approval program allows FDA to approve drugs for serious conditions to fill an unmet medical need based on a surrogate endpoint, i.e., a result that is reasonably likely to predict a clinical benefit to patients. Additional clinical trials are required to confirm Trodelvy’s clinical benefit, and the FDA can remove the drug from the market if the confirmatory trial does not show that the drug provides clinical benefit.

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.