Intranasal COVID-19 vaccine induces respiratory memory T cells and protects K18-hACE mice against SARS-CoV-2 infection.

Current COVID-19 vaccines prevent severe disease, but do not induce mucosal immunity or prevent infection with SARS-CoV-2, especially with recent variants. Furthermore, serum antibody responses wane soon after immunization. We assessed the immunogenicity and protective efficacy of an experimental COVID-19 vaccine based on the SARS-CoV-2 Spike trimer formulated with a novel adjuvant LP-GMP, comprising TLR2 and STING agonists. We demonstrated that immunization of mice twice by the intranasal (i.n.) route or by heterologous intramuscular (i.m.) prime and i.n. boost with the Spike-LP-GMP vaccine generated potent Spike-specific IgG, IgA and tissue-resident memory (TRM) T cells in the lungs and nasal mucosa that persisted for at least 3 months. Furthermore, Spike-LP-GMP vaccine delivered by i.n./i.n., i.m./i.n., or i.m./i.m. routes protected human ACE-2 transgenic mice against respiratory infection and COVID-19-like disease following lethal challenge with ancestral or Delta strains of SARS-CoV-2. Our findings underscore the potential for nasal vaccines in preventing infection with SARS-CoV-2 and other respiratory pathogen.

SAR442085, a novel anti-CD38 antibody with enhanced antitumor activity against multiple myeloma.

Anti-CD38 monoclonal antibodies (mAbs) represent a breakthrough in the treatment of multiple myeloma (MM), yet some patients fail to respond or progress quickly with this therapy, highlighting the need for novel approaches. In this study we compared the preclinical efficacy of SAR442085, a next-generation anti-CD38 mAb with enhanced affinity for activating Fcγ receptors (FcγR), with first-generation anti-CD38 mAb daratumumab and isatuximab. In surface plasmon resonance and cellular binding assays, we found that SAR442085 had higher binding affinity than daratumumab and isatuximab for FcγRIIa (CD32a) and FcγRIIIa (CD16a). SAR442085 also exhibited better in vitro antibody-dependent cellular cytotoxicity (ADCC) against a panel of MM cells expressing variable CD38 receptor densities including MM patients' primary plasma cells. The enhanced ADCC of SAR442085 was confirmed using NK-92 cells bearing low and high affinity FcγRIIIa (CD16a)-158F/V variants. Using MM patients' primary bone marrow cells, we confirmed that SAR442085 had an increased ability to engage FcγRIIIa, resulting in higher natural killer (NK) cell activation and degranulation against primary plasma cells than preexisting Fc wild-type anti-CD38 mAbs. Finally, using huFcgR transgenic mice that express human Fcγ receptors under the control of their human regulatory elements, we demonstrated that SAR442085 had higher NK cell-dependent in vivo antitumor efficacy and better survival than daratumumab and isatuximab against EL4 thymoma or VK*MYC myeloma cells overexpressing human CD38. These results highlight the preclinical efficacy of SAR442085 and support the current evaluation of this next-generation anti-CD38 antibody in phase I clinical development in patients with relapsed/refractory MM.

BMFPs, a versatile therapeutic tool for redirecting a preexisting Epstein-Barr virus antibody response toward defined target cells.

Industrial production of therapeutic monoclonal antibodies is mostly performed in eukaryotic-based systems, allowing posttranslational modifications mandatory for their functional activity. The resulting elevated product cost limits therapy access to some patients. To address this limitation, we conceptualized a novel immunotherapeutic approach to redirect a preexisting polyclonal antibody response against Epstein-Barr virus (EBV) toward defined target cells. We engineered and expressed in bacteria bimodular fusion proteins (BMFPs) comprising an Fc-deficient binding moiety targeting an antigen expressed at the surface of a target cell, fused to the EBV-P18 antigen, which recruits circulating endogenous anti-P18 IgG in EBV+ individuals. Opsonization of BMFP-coated targets efficiently triggered antibody-mediated clearing effector mechanisms. When assessed in a P18-primed mouse tumor model, therapy performed with an anti-huCD20 BMFP significantly led to increased survival and total cancer remission in some animals. These results indicate that BMFPs could represent potent and useful therapeutic molecules to treat a number of diseases.

[MAbs: the history of a basic research or the curiosity as a source of wealth]. / Les anticorps monoclonaux - L'histoire d'une recherche fondamentale ou la curiosité comme source de richesse1.

In 2019, monoclonal antibodies are a worldwide annual business worth of more than 100 billions USD (i.e., about 90 billions €). In addition to their use in the clinics, monoclonal antibodies are also used for diagnosis and remain highly valuable tools for academic basic and translational research. Forty-four years after the seminal publication of Georges Köhler and César Milstein, dozens of meetings and seminars focusing on various aspects of mAbs are held annually all around the world. But forty-four years later, the scientific works and efforts that have made possible this scientific breakthrough are gradually forgotten and, for many, monoclonal antibodies are no more than a multi-million USD business alike any other big business, guided by financial markets and the results of on-going clinical trials… Time has now come for acknowledging and paying tribute to all these scientists involved in basic research, to these researchers passionate about science, some famous, some forgotten, scattered all over the world. They explored during the 20th century the frontiers of unknown and generated a knowledge that allowed the emergence of a technique that translated finally into what is one of the greatest therapeutic revolution of the modern era.

TITLE: Les anticorps monoclonaux - L'histoire d'une recherche fondamentale ou la curiosité comme source de richesse1. ABSTRACT: En 2019, les anticorps monoclonaux (Acm) vont représenter un marché mondial annuel de plus de cent milliards de dollars, soit près de 90 milliards d'euros. Outre leur utilisation en clinique, les anticorps monoclonaux sont utilisés également dans de nombreux tests diagnostiques et sont toujours des outils précieux pour la recherche fondamentale et appliquée. Quarante-quatre ans après la publication de Georges Köhler et César Milstein [1], des dizaines de congrès et séminaires de toute nature sur les anticorps monoclonaux se tiennent annuellement à travers le monde. Mais 44 ans plus tard, les travaux scientifiques qui ont amené à cette publication sont peu à peu oubliés et, dans bien des esprits, les anticorps monoclonaux ne sont qu'un business d'un multi-milliard euros/dollars comme un autre, déterminé par les marchés financiers et les résultats des derniers essais cliniques… Il est grand temps de rendre hommage à toute une génération de chercheurs fondamentalistes, à ces fous de science du xx e siècle, à ces chercheurs connus et souvent désormais méconnus, disséminés aux quatre coins du monde, qui ont exploré les frontières de l'inconnu d'alors et qui ont modelé et ciselé un savoir qui a débouché sur une technique d'obtention de molécules qui ont permis l'une des plus grandes révolutions thérapeutiques de ces vingt-cinq dernières années.