A monoclonal antibody targeting a large surface of the receptor binding motif shows pan-neutralizing SARS-CoV-2 activity.

Here we report the characterization of 17T2, a SARS-CoV-2 pan-neutralizing human monoclonal antibody isolated from a COVID-19 convalescent individual infected during the first pandemic wave. 17T2 is a class 1 VH1-58/κ3-20 antibody, derived from a receptor binding domain (RBD)-specific IgA+ memory B cell, with a broad neutralizing activity against former and new SARS-CoV-2 variants, including XBB.1.16 and BA.2.86 Omicron subvariants. Consistently, 17T2 demonstrates in vivo prophylactic and therapeutic activity against Omicron BA.1.1 infection in K18-hACE2 mice. Cryo-electron microscopy reconstruction shows that 17T2 binds the BA.1 spike with the RBD in "up" position and blocks the receptor binding motif, as other structurally similar antibodies do, including S2E12. Yet, unlike S2E12, 17T2 retains its neutralizing activity against all variants tested, probably due to a larger RBD contact area. These results highlight the impact of small structural antibody changes on neutralizing performance and identify 17T2 as a potential candidate for future clinical interventions.

Advances in the Treatment of Gastroenteropancreatic Neuroendocrine Carcinomas: Are we Moving Forward?

Poorly differentiated gastroenteropancreatic neuroendocrine carcinomas are aggressive neoplasms of challenging clinical management. A small proportion of patients with early-stage disease may achieve long-term survival, but the majority of patients present with rapidly lethal metastatic disease. Current standard of care still follows the treatment paradigm of small cell lung cancer, a far more common G3 neuroendocrine neoplasm, although emerging molecular and clinical data increasingly question this approach. In this article, we will briefly summarize epidemiology and prognosis of gastroenteropancreatic neuroendocrine carcinomas to emphasize the very low incidence, aggressive nature, and orphan status of this tumor entity. We will also discuss the current pathological classification and its limitations, as well as recent data on their differential biological background compared with small cell lung cancer, and its potential implications for patients care. Then, we will review the standard of care of systemic therapy, basically focused on platinum-based cytotoxic chemotherapy, including some recent randomized trials providing evidence regarding efficacy of irinotecan vs etoposide platinum doublets. Finally, we will present a comprehensive overview of novel therapeutic strategies in current clinical development, including recently reported data on immunotherapy, tumor-agnostic therapies (microsatellite instability, high tumor mutational burden, NTRK and RET gene fusions, BRAF or KRAS inhibitors), and additional treatment strategies targeting other tumor vulnerabilities (ie, Notch pathway, novel targets for radioligand therapy), and provide some insights regarding unmet needs and future perspectives to improve patient's care and prognosis.

CryoEM of Viral Ribonucleoproteins and Nucleocapsids of Single-Stranded RNA Viruses.

Single-stranded RNA viruses (ssRNAv) are characterized by their biological diversity and great adaptability to different hosts; traits which make them a major threat to human health due to their potential to cause zoonotic outbreaks. A detailed understanding of the mechanisms involved in viral proliferation is essential to address the challenges posed by these pathogens. Key to these processes are ribonucleoproteins (RNPs), the genome-containing RNA-protein complexes whose function is to carry out viral transcription and replication. Structural determination of RNPs can provide crucial information on the molecular mechanisms of these processes, paving the way for the development of new, more effective strategies to control and prevent the spread of ssRNAv diseases. In this scenario, cryogenic electron microscopy (cryoEM), relying on the technical and methodological revolution it has undergone in recent years, can provide invaluable help in elucidating how these macromolecular complexes are organized, packaged within the virion, or the functional implications of these structures. In this review, we summarize some of the most prominent achievements by cryoEM in the study of RNP and nucleocapsid structures in lipid-enveloped ssRNAv.

Perioperative Chemotherapy for Liver Metastasis of Colorectal Cancer: Lessons Learned and Future Perspectives.

OPINION STATEMENT: Colorectal cancer (CRC) is a major public health problem and the 2nd leading-cause of cancer-related death worldwide. Around 30% of patients present with metastatic disease and 50% of those with early disease will eventually relapse. The metastatic spread occurs mainly to the liver, which is the exclusive site in 30-40% of the cases. Surgery is the main curative option for liver recurrence, but only one out of five patients are eligible for resection. Moreover, even if surgery is feasible, recurrence rate is high, occurring in up to 75% of patients. Therefore, additional treatment to improve these disappointing outcomes has been sought. Adjuvant and perioperative chemotherapy aim to eradicate early micrometastatic disease, decreasing recurrence rates, and improving survival outcomes. Different chemotherapy regimens, mainly extrapolated from the adjuvant experience, have showed conflicting results, with improvements in disease free but not in overall survival. The addition of targeted therapies to chemotherapy has improved response rates and resectability when administered preoperatively, but did not have an impact on survival in the adjuvant setting. There is a need to critically synthetize the available evidence on perioperative and conversion therapy from the past years, and appraise areas of current research and potential future directions.

Human α-Galactosidase A Mutants: Priceless Tools to Develop Novel Therapies for Fabry Disease.

Fabry disease (FD) is a lysosomal storage disease caused by mutations in the gene for the α-galactosidase A (GLA) enzyme. The absence of the enzyme or its activity results in the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), in different tissues, leading to a wide range of clinical manifestations. More than 1000 natural variants have been described in the GLA gene, most of them affecting proper protein folding and enzymatic activity. Currently, FD is treated by enzyme replacement therapy (ERT) or pharmacological chaperone therapy (PCT). However, as both approaches show specific drawbacks, new strategies (such as new forms of ERT, organ/cell transplant, substrate reduction therapy, or gene therapy) are under extensive study. In this review, we summarize GLA mutants described so far and discuss their putative application for the development of novel drugs for the treatment of FD. Unfavorable mutants with lower activities and stabilities than wild-type enzymes could serve as tools for the development of new pharmacological chaperones. On the other hand, GLA mutants showing improved enzymatic activity have been identified and produced in vitro. Such mutants could overcome several complications associated with current ERT, as lower-dose infusions of these mutants could achieve a therapeutic effect equivalent to that of the wild-type enzyme.

Lurbinectedin in the treatment of relapsed small cell lung cancer.

Lurbinectedin is a marine-derived drug that inhibits transcription, a process that is frequently dysregulated in small cell lung cancer. The activity of lurbinectedin has been studied in many solid tumors, showing not only promising results but also a favorable safety profile. In relapsed small cell lung cancer, the drug has shown encouraging activity both as a single agent and in combination with doxorubicin, paclitaxel or irinotecan. The USA FDA has recently granted accelerated approval to lurbinectedin monotherapy in this setting. This article provides an update on available data and ongoing studies of lurbinectedin in small cell lung cancer, including Phase I combination trials, the basket Phase II trial and the ATLANTIS Phase III trial.

Lay abstract Lung cancer is currently responsible for a large number of cancer deaths worldwide. Small cell lung cancer (SCLC) is considered the most aggressive subtype of lung cancer. When a patient presents with extensive SCLC, first-line treatment needs to be used. The most appropriate treatment option for the patient is selected; however, it is possible for the cancer to continue to get worse, even over a brief period of time. The patient will then be given another treatment; however, studies on the effectiveness of classical second-line drugs are scarce. For this reason, new therapies for SCLC are in development. One of these treatments is a marine-derived drug called lurbinectedin, which shows promising activity in some solid tumors, such as extensive SCLC, after failure of first-line treatment. Here the authors present the results of the main trials related to the activity of lurbinectedin either alone or in combination with other drugs for this type of cancer.