Explore the vast range of titles available.

Isatuximab is a monoclonal antibody targeting the transmembrane receptor and ectoenzyme CD38, a protein highly expressed on hematological malignant cells, including those in multiple myeloma (MM). Upon binding to CD38-expressing MM cells, isatuximab is thought to induce tumor cell killing via fragment crystallizable (Fc)-dependent mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), as well as via direct Fc-independent mechanisms. Here, these mechanisms of action were investigated in MM and diffuse large B-cell lymphoma (DLBCL) cell lines, as well as in peripheral blood mononuclear cells derived from healthy donors, and in MM patient-derived samples. Our findings show that isatuximab-mediated cytotoxicity occurred primarily via ADCC and ADCP in MM cell lines and via ADCC and apoptosis in DLBCL cell lines expressing high levels of CD38. We identified the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway and MM cell-secreted transforming growth factor-beta (TGF-β) as tumor cell-related features that could suppress CD38-mediated ADCC. Furthermore, we established that isatuximab can directly activate natural killer (NK) cells and promote NK cell-mediated cytotoxicity via crosslinking of CD38 and CD16. Finally, isatuximab-induced CDC was observed in cell lines with high CD38 receptor density (>250,000 molecules/cell) and limited expression of inhibitory complement regulatory proteins (CD46, CD55, and CD59; <50,000 molecules/cell). Taken together, our findings highlight mechanistic insights for isatuximab and provide support for a range of combination therapy approaches that could be tested for isatuximab in the future.

2020 was a very unusual year due the COVID-19 pandemic that has caused many fatalities and is disrupting practically every aspect of our lives. It is unprecedented to see PubMed literature entries on a subject go from 0 to ~ 90,000 in a year. This effect is a direct result of the necessity of the scientific community to share data and insights generated worldwide. One of the potential unintended consequences of the sheer volume of literature in such a short amount of time is that many of it is not carefully peer-reviewed and vetted, making it difficult to sieve through information and understand it in order to allow informed decision making.In this thesis, we conduct a critical evaluation of the scientific evidence and present the current landscape for COVID-19 therapeutics. We first discuss efforts to repurpose old drugs and to discover novel drugs against COVID-19. We then evaluate the clinical evidence of the most promising drug candidates that are approved or recommended for emergency use by relying on high quality systematic reviews as guided by the AMSTAR-2 tool and/or latest clinical evidence if no systematic reviews are available. Lastly, we discuss pressing challenges of the COVID-19 pandemic and provide conclusions and recommendations for future work.