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Anti-Drug Antibodies

Over 30 years since the approval of the first therapeutic monoclonal antibody (mAb) for clinical use, the mAb industry has expanded exponentially and comprises the fastest growing class of pharmaceutics.  While mAbs hold significant promise for improving human health, repeated administration of mAb often leads to the induction of undesirable Anti-Drug Antibodies (ADAs), which can interfere with or neutralize the effect of the drug. The generation of ADAs towards mAbs can also be associated with important clinical adverse reactions, including alterations in drug pharmacokinetics and bioavailability, reductions in drug efficacy, cross-reaction with endogenous proteins and inhibition of the latter’s physiological function, and allergic drug reactions and other safety-related adverse events. However, the mechanisms that lead to induction of ADAs and the molecular composition of the ADAs are unknown.

TNFa antagonist, are routinely used to treat certain types of arthritis, inflammatory bowel diseases, and psoriasis. However, up to 40% of treated patients lose response to the drug due to the development of Anti-Drugs Antibodies (ADA). We have used Infliximab and Adalimumab as a model to investigate molecular aspects related to the development of ADAs. We developed a new immunoassay to determine ADA level and their neutralizing capacity. The developed immunoassay utilizes a modified version of the drug, enabling the detection of serum ADAs while maintaining low background signals. Moreover, we have found that drug infusion mounts a vaccine like response reflected in a rapid rise of lymphocytes 7-10 days post-infusion. Isolated lymphocytes post-drug infusion and drug-specific serum antibodies are isolated and their repertoire features are determined by Next Generation Sequencing and shot-gun bottom-up proteomics. 

Maternal Immunization

Many vaccine-preventable diseases, like influenza, pertussis, and tetanus cause substantial morbidity and mortality in pregnant women, newborns and infants. Immunization during pregnancy has the potential to provide protection to the newborn and infant by the transplacental transfer of vaccine-specific maternal antibodies. However, the immunobiology underlying immunization during pregnancy, that leads to the protection of the newborn are not understood. Current vaccine formulations were designed for and tested in non-pregnant populations; yet substantial immune modulations take place during different stages of pregnancy and potentially can impact the humoral response following maternal immunzation. We thus have insufficient data on quantity and quality of the immune response during pregnancy and how this relates to immunity provided from the mother to the newborn. First, we hypothesize that the nature and breadth of the humoral immune response following vaccination differs in pregnant and non-pregnant vaccinees. Next, we hypothesize that the vaccine-specific antibodies that cross the plaecenta, comprise distinct repertoire features thus, the placenta functions as a differential barrier for antibody transfer.  To test these hypotheses, we use proteomic and genomic/transcriptomic measurements of antibody repertoires in the maternal and cord blood compartments. The measurements will be based on antibody clonal diversity/frequency, V(D) J gene germline usage and SHM, where we expect to find changes in i) vaccine-specific B cell frequency, antibody clonal diversity, germline usage and SHM in pregnant women and ii) distinct repertoire features in the transplacental vaccine-specific antibody compartment compared the maternal compartment. We will utilize deep sequencing and proteomic technologies to provide, for the first time, insight into the immunobiology of a promising intervention aimed to prevent early life infectious morbidity and mortality and establish new research avenues for vaccine research in vulnerable populations.

Congenital HCMV

Human cytomegalovirus (HCMV) is the most common viral infection in newborns worldwide and the leading cause of congenital neurosensorial disease of infectious origin. The development of prenatal diagnosis and preventive measures for congenital HCMV disease is limited by our poor understanding of the mechanisms involved in the vertical transmission and pathogenesis of congenital infection. Notably, the transmission rate from a woman who contracts primary HCMV during pregnancy is between 30 and 50%. Following transmission, 10-25% of newborns show signs of congenital HCMV. These rates may be partially explained by the immune IgG response to HCMV envelope glycoproteins, which is likely a key determinant of viral control. However a partial immune response could also participate in immunopathological responses at the placental level. Thus, there is currently a clearly unmet clinical need to better understand the viral and host immune responses, in order to evaluate the risk of congenital HCMV infection and disease. The objectives of this project are to 1) use multi-parametric analyses to identify host-pathogen components associated with increased probability of congenital HCMV transmission and postpartum sequelae; 2) characterise the interactions between IgG, HCMV variants and innate immune cells at the placental level. Taken together, achieving these objectives will allow developing new diagnostic approaches to evaluate the risk for congenital HCMV infection, predict clinical outcome pre- and postpartum, and avoid unnecessary medical interventions and unnecessary pregnancy termination. We will analyze the anti HCMV antibody repertoire in relation to transmission and disease, using novel proteomic and genomic approaches.  These studies will potentially uncover for the first time the connection between HCMV mother to fetus transmission and pathogenesis in the neonate. The findings will directly facilitate prenatal screening, prediction, and prevention of congenital HCMV disease and will inform studies of other congenital infections such as Zika virus.  

Anti-Bacterial Immunotherapy

The emergence of MDR bacterial strains, especially those of pathogenic bacteria, has very serious medical and clinical implications, and is a growing public health concern worldwide. In high-income countries where antibiotics are heavily used in the community and agriculture, the strong selection pressure and non-completed antibiotic regimens have resulted in the emergence and dominance of MDR strains, forcing a shift to more expensive and broad-spectrum antibiotics.

Development of new MAbs for pharmaceutical development has increased substantially during the recent years. One major unmet need is the development of new antibacterial MAbs as alternatives to antibiotics, especially in light of the emergence of MDR bacteria. Recent developments and accumulated data are converging to turn antibacterial MAbs into powerful therapeutics for fighting infections. Anti-bacterial MAbs offer key benefits over conventional antibiotics. a) Unlike antibiotics, they do not provide selection pressure feedback to the genome, hence are less likely to induce resistance among bacteria.

b) MAbs are designed against bacterial pathogen targets and thus should not perturb the nonpathogenic microbiota which lack the target. c) The MAb can be injected as a single-dose regimen when urgently needed, or concomitantly with traditional antibiotics, which could have synergistic bacteria-clearing effects. This project aims to provide a novel therapeutic monoclonal antibody (MAb) to treat infections by multidrug-resistant (MDR) pathogenic bacteria. Specific aims:

(i)To establish the molecular mechanism of action (MoA) of the MAb including the cell biology underlining its inhibitory mechanism in an ex-vivo bacterial model system.

(ii)To advance the MAb to the stage of development and clinical trials. 

Tumor Infiltrating B cells (TIL-B)

Currently, tumor-infiltrating B cells (TIL-B) have been recognized as a new hallmark of several types of cancers. The function seems to be controversial, either with positive, negative, or no significance in the prediction and prognosis. Moreover, B-cell infiltrates regulate tumor process through productions of antibodies. The interactions with other lymphocytes and programmed death-1/PD-1 ligand axis is also documented. However, B cells infiltrating into solid tumors are poorly investigated. Whether their potential as antitumor comes from either the antigen presentation or the antibody production capacity or both, is unknown.

In this project, we aim to investigate the role of B cells in the tumor microenvironment and shed light on the mechanisms involved in their anti-tumor activity. We utilize NGS and RNA-seq to profile the TIL-B and aim to shed light on their potential leads for the development of new therapeutic strategies.

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