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FDA grants first approval to tafasitamab-cxix

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On July 31, 2020, the FDA approved Monjuvi® (tafasitamab-cxix) in combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant. FDA had granted Monjuvi® an orphan drug designation for this indication, as well as Fast Track and Breakthrough Therapy designations, and the biologics license application was given a Priority Review. Monjuvi® was approved under FDA’s accelerated approval regulations, which require that further adequate and well-controlled studies/clinical trials be done to verify and describe clinical benefit. A marketing application for tafasitamab is undergoing evaluation by the European Medicines Agency.

Tafasitamab-cxix is a humanized cytolytic CD19-targeting monoclonal antibody that contains a IgG1/2 hybrid Fc-domain with 2 amino acid substitutions to modify the Fc-mediated functions of the antibody. Upon binding to CD19, tafasitamab-cxix mediates B-cell lysis through apoptosis and immune effector mechanisms, including antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis.

FDA’s approval was based on the efficacy of Monjuvi® in combination with lenalidomide followed by Monjuvi® as monotherapy demonstrated in L-MIND (NCT02399085), an open label, multicenter single arm trial. Results from the study showed an overall response rate of 55% (primary endpoint), including a complete response rate of 37% and a partial response rate of 18%. The median duration of response was 21.7 months. The approval was granted to MorphoSys US Inc. MorphoSys and Incyte will co-commercialize the product in the United States. Incyte has exclusive commercialization rights outside the United States.

Antibodies to watch

Tafasitamab-cxix is the 6th antibody therapeutic to be granted a first approval in the US in 2020. Marketing applications for a substantial number of investigational antibody therapeutics are currently undergoing either FDA or EMA review, including:

  • Ansuvimab, a human IgG1 targeting Ebola virus glycoprotein for Ebola virus infection
  • Inolimomab, a mouse IgG1 targeting CD25 for host vs. graft disease
  • Bimekizumab, a humanized IgG1 targeting IL-17A, F for psoriasis
  • Omburtamab, a murine IgG1 targeting B7-H3 for CNS/leptomeningeal metastases from neuroblastoma
  • Tralokinumab, a human IgG4 targeting IL-13 for atopic dermatitis
  • Evinacumab, a human IgG4 targeting angiopoietin-like 3 for homozygous familial hypercholesterolemia
  • Sutimlimab, a humanized IgG4 targeting C1s for cold agglutinin disease
  • Aducanumab, a human IgG1 targeting amyloid beta for Alzheimer’s disease
  • Teplizumab, a humanized IgG1 targeting CD3 for Type 1 diabetes
  • Dostarlimab, a humanized IgG4 targeting PD-1 for endometrial cancer
  • Tanezumab, a humanized IgG2 targeting nerve growth factor for osteoarthritis pain
  • Margetuximab, a chimeric IgG1 targeting HER2 for HER2+ breast cancer
  • Naxitamab, a humanized IgG1 targeting GD2 for high-risk neuroblastoma and refractory osteomedullary disease
  • Belantamab mafodotin, a humanized IgG1 antibody-drug conjugate targeting BCMA for multiple myeloma
  • Oportuzumab monatox, a humanized scFv immunotoxin targeting EpCAM for bladder cancer
  • REGNEB3 (odesivimab, maftivimab, atoltivimab), a mixture of 3 human IgG1 targeting Ebola virus for Ebola virus infection
  • Narsoplimab, a human IgG4 targeting MASP-2 for hematopoietic stem cell transplant-associated thrombotic microangiopathies
  • Satralizumab, a humanized IgG2 targeting IL-6R  for neuromyelitis optica and neuromyelitis optica spectrum disorders

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. The table, which is located in the Web Resources section of the Society’s website, can be downloaded in Excel format. Information about other antibody therapeutics that may enter regulatory review in 2020 can be found in ‘Antibodies to watch in 2020’.

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Will SARS-CoV-2 introduce a new era for subunit vaccines?

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Written by: Gunnveig Grødeland, PhD, University of Oslo and Oslo University Hospital.

Effective control of Covid-19 is dependent upon development of protective and safe vaccines. At present, there are many different vaccine formats against SARS-CoV-2 in clinical development, with the more advanced already in clinical Phase III studies. A remaining challenge, however, is that we still do not have a clear understanding of what constitutes the most relevant type of immunity for protection against Covid-19, and what would be the best strategy for induction of such protection.

A serological survey of over 35,000 households in Spain has demonstrated that an overall 5% of the population has antibodies against SARS-CoV-2, with a higher prevalence of 10% around Madrid and lower in coastal areas (1). Spain has been one of the more severely Covid-19 affected countries in Europe. The fairly low incidence of antibodies in the Spanish population therefore implies that we cannot rely on herd immunity to develop naturally from the present pandemic. Further, the prevalence of SARS-CoV-2 specific antibodies in populations from the epicenters of New York and Lombardy has been estimated to be about 20-25% (2,3). It is not yet clear which antigens and epitopes the induced antibodies are directed against, but there are indications that the antibodies may have a limited capacity for neutralization (4).

During the previous SARS-CoV-1 outbreak in 2002/03, it was demonstrated that antibodies induced against immunodominant sites of the Spike protein were not neutralizing (5). It is also known that when neutralizing antibodies are induced they typically bind to the receptor binding domain of Spike, but also that such antibodies could potentially induce conformational changes in Spike due to mimicking of the ACE-2 receptor and as such potentially enhance viral infection (6). Careful design would therefore be needed for utilization of Spike as a vaccine antigen.

While most vaccines presently in development against SARS-CoV-2 aim for induction of antibodies, cellular immunity can also award protection against disease. Interestingly, a large part of the population have T cells that are reactive against different SARS-CoV-2 proteins even in the absence of a SARS-CoV-2 infection. These T cells are mostly CD4+, and likely originated from previous infections with the “common cold” coronaviruses (7,8). However, it is not yet clear to what degree their presence can reduce development of severe Covid-19 disease.

How should we proceed with vaccine development in a situation where the correlate of protection is not clear?

Pandemics may emerge when a novel pathogen has acquired the ability to transmit efficiently from human to human. As is the case for SARS-CoV-2, we should expect many unknowns when a new pandemic erupts. Vaccination remains the best preventive strategy, but how can one efficiently design vaccines when it is not clear what type of immune responses will be more important for protection? The only answer today is to simultaneously develop many different vaccine formats, compare their strengths and weaknesses, and select the best-fit candidate for vaccination of the population. For this to work, it is important that researchers share both promising and negative results for their particular vaccine format. It is my hope that this strategy will secure a vaccine ready to be large-scale deployed against SARS-CoV-2 during 2021.

We can be certain that SARS-CoV-2 will not be the last pandemic challenge facing the world. It is still unclear what will happen during this fall, but alongside taming the present outbreak, we should try to generate knowledge and strategies that may be of use for quenching the next pandemic emergence caused by an unknown pathogen X. This includes both strategies for managing transmission in society, development of treatment strategies that can be used for limiting replication across different viral families, as well as development of vaccine platforms that can be readily adapted for tailored induction of particular types of immunity.

A new era for subunit vaccines?

Interestingly, a majority of the vaccine formats presently in development against SARS-CoV-2 are subunit vaccines, meaning that they contain only selected viral antigens. At present, there are no genetic subunit vaccine licensed for use in humans, but there are a few protein based subunit vaccines available (e.g., Flublok by Sanofi, Recombivax by Merck).

Subunit vaccines have typically been hampered by reduced immunogenicity, necessitating the combined use of an adjuvant or alternative strategies for enhancing vaccine efficacy. However, their safety profiles and ease of production nevertheless makes subunit vaccines ideal for pandemic prevention.

The large amount of research presently going into development and clinical evaluation of different subunit vaccines is unprecedented. Thus, the ongoing SARS-CoV-2 pandemic may turn out to be the breaking point where subunit vaccines establish themselves as the preferred alternative to conventional inactivated or attenuated vaccines.

Subunit vaccines rely on rational selection and design of selected antigens. As such, immune responses can be steered towards antigenic regions more relevant for development of protective immunity. The better we understand human immunology, the better subunit vaccines we can design. For the future, we could be able to assign the relevant correlate of protection by examining shared pathogen traits, and then design vaccines specifically tailored for induction of the corresponding type of immunity. In the meantime, we will likely fare better by aiming a bit more broadly, and develop subunit vaccines that can induce both antibody and T cell responses.

References

1.    Pollan, M., B. Perez-Gomez, R. Pastor-Barriuso, J. Oteo, M. A. Hernan, M. Perez-Olmeda, J. L. Sanmartin, A. Fernandez-Garcia, I. Cruz, L. N. Fernandez de, M. Molina, F. Rodriguez-Cabrera, M. Martin, P. Merino-Amador, P. J. Leon, J. F. Munoz-Montalvo, F. Blanco, and R. Yotti. 2020. Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study. Lancet.

2.    Percivalle, E., G. Cambie, I. Cassaniti, E. V. Nepita, R. Maserati, A. Ferrari, M. R. Di, P. Isernia, F. Mojoli, R. Bruno, M. Tirani, D. Cereda, C. Nicora, M. Lombardo, and F. Baldanti. 2020. Prevalence of SARS-CoV-2 specific neutralising antibodies in blood donors from the Lodi Red Zone in Lombardy, Italy, as at 06 April 2020. Euro. Surveill 25.

3.    Stadlbauer D, Tan J, Jiang K, Hernandez M.M, Fabre S, Amanat F, Teo C, Arunkumar G, McMahon M, Jhang J, Nowak MD, Simon V, Sordillo EM, Bakel H, and Krammer F. 2020. Seroconversion of a city: Longitudinal monitoring of SARS-CoV-2 seroprevalence 1 in New York City. medRxiv preprint.

4.    Robbiani, D. F., C. Gaebler, F. Muecksch, J. C. C. Lorenzi, Z. Wang, A. Cho, M. Agudelo, C. O. Barnes, A. Gazumyan, S. Finkin, T. Hagglof, T. Y. Oliveira, C. Viant, A. Hurley, H. H. Hoffmann, K. G. Millard, R. G. Kost, M. Cipolla, K. Gordon, F. Bianchini, S. T. Chen, V. Ramos, R. Patel, J. Dizon, I. Shimeliovich, P. Mendoza, H. Hartweger, L. Nogueira, M. Pack, J. Horowitz, F. Schmidt, Y. Weisblum, E. Michailidis, A. W. Ashbrook, E. Waltari, J. E. Pak, K. E. Huey-Tubman, N. Koranda, P. R. Hoffman, A. P. West, Jr., C. M. Rice, T. Hatziioannou, P. J. Bjorkman, P. D. Bieniasz, M. Caskey, and M. C. Nussenzweig. 2020. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature.

5.    He, Y., Y. Zhou, H. Wu, B. Luo, J. Chen, W. Li, and S. Jiang. 2004. Identification of immunodominant sites on the spike protein of severe acute respiratory syndrome (SARS) coronavirus: implication for developing SARS diagnostics and vaccines. J. Immunol. 173: 4050-4057.

6.    Yang, Z. Y., H. C. Werner, W. P. Kong, K. Leung, E. Traggiai, A. Lanzavecchia, and G. J. Nabel. 2005. Evasion of antibody neutralization in emerging severe acute respiratory syndrome coronaviruses. Proc. Natl. Acad. Sci. U. S. A 102: 797-801.

7.    Grifoni, A., D. Weiskopf, S. I. Ramirez, J. Mateus, J. M. Dan, C. R. Moderbacher, S. A. Rawlings, A. Sutherland, L. Premkumar, R. S. Jadi, D. Marrama, A. M. de Silva, A. Frazier, A. F. Carlin, J. A. Greenbaum, B. Peters, F. Krammer, D. M. Smith, S. Crotty, and A. Sette. 2020. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 181: 1489-1501.

8.    Le Bert N, Tan TA, Kunasegaran K, Tham CYL, Hafezi M, Chia A, Chng M, Lin M, Tan N, Linster M, Chia WN, Chen MIC, Wang LF, Ooi EE, Lalimuddin S, Tambyah PA, Low JGH, Tan YJ, and Bertoletti A. 2020. Different pattern of pre-existing SARS-COV-2 specific T cell immunity in SARS-recovered and uninfected individuals. bioRxiv preprint.

 

AIRR-C Membership Campaign

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On behalf of the AIRR Community Executive Sub-committee, we announce the AIRR Community Membership Campaign for 2020-2021. Current AIRR-C members are now considered “Legacy” members until they pay their annual dues. Please support the AIRR Community Membership Campaign today.

For further information about our ongoing initiatives, Working Groups, Sub-committees and membership benefits follow this link. AIRR Community Membership levels for 2020/2021 include:

  • AIRR-C Standard membership fee is $100 per year
  • AIRR-C Postdoc membership is free for up to 2 years
  • AIRR-C Student membership is free for up to 2 years

Thank you for paying your membership dues and for all that you do for the AIRR Community!

Nina Luning Prak, MD, PhD
AIRR Community Executive Sub-committee Chair

COVID-19 data repository now available

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Interested in antibody/B-cell and T-cell receptor sequences derived from COVID-19 patients?

The iReceptor Project’s COVID-19 specific data repository has > 180 million sequences of AIRR-seq data (massive repertoires of antibody/B-cell and T-cell receptor sequences) from 5 studies of COVID-19 patients.

The data are available for download in a standard AIRR.tsv format, which makes it easy to import the data into many AIRR.seq analysis programs, and more COVID-19 studies will be available soon.

The iReceptor Gateway allows researchers to compare the COVID-19 data to ~2.5 billion immune receptor sequences from other infectious diseases, cancer studies, autoimmune patients and healthy control individuals. The Gateway can be used, for example, to determine whether antibodies discovered in COVID-19 patients are “public” (appearing in many individuals from many conditions including healthy controls) or “private” (only appearing in patients exhibiting severe COVID-19 reactions). This information and other repertoire comparisons should greatly accelerate the development of anti-COVID therapeutics and vaccines.

Present functionalities include:

  • Search for repertoires satisfying certain metadata (e.g. find all AIRR-seq repertoires from ovarian cancer studies)
  • Search for all repertoires that contain specific CDR3 sequences
  • Search identified repertoires for sequences derived from particular V, D, and J genes and alleles
  • Download sequences from these repertoires in AIRR.tsv format, easily importable to other AIRR-seq analysis tools

The iReceptor Gateway follows the protocols and standards developed by the AIRR-Community to facilitate sharing and analysis of AIRR-seq data. The AIRR Community, part of The Antibody Society, is a grassroots group of immunologists, immunogeneticists and computer scientists dedicated to sharing data through the AIRR Data Commons.  The iReceptor Project implements this Data Commons, and the development of the COVID-specific repository on the iReceptor Gateway follows the call from the AIRR Community for increased sharing of data during the coronavirus crisis.

Researchers interested in sharing data or exploring the AIRR Data Commons through the open iReceptor Gateway should visit www.ireceptor.org and contact support@ireceptor.org for an account.

iReceptor is a member of the iReceptor Plus Consortium.