Research Progress and Applications of Multivalent, Multispecific and Modified Nanobodies for Disease Treatment.

Recombinant antibodies such as nanobodies are progressively demonstrating to be a valid alternative to conventional monoclonal antibodies also for clinical applications. Furthermore, they do not solely represent a substitute for monoclonal antibodies but their unique features allow expanding the applications of biotherapeutics and changes the pattern of disease treatment. Nanobodies possess the double advantage of being small and simple to engineer. This combination has promoted extremely diversified approaches to design nanobody-based constructs suitable for particular applications. Both the format geometry possibilities and the functionalization strategies have been widely explored to provide macromolecules with better efficacy with respect to single nanobodies or their combination. Nanobody multimers and nanobody-derived reagents were developed to image and contrast several cancer diseases and have shown their effectiveness in animal models. Their capacity to block more independent signaling pathways simultaneously is considered a critical advantage to avoid tumor resistance, whereas the mass of these multimeric compounds still remains significantly smaller than that of an IgG, enabling deeper penetration in solid tumors. When applied to CAR-T cell therapy, nanobodies can effectively improve the specificity by targeting multiple epitopes and consequently reduce the side effects. This represents a great potential in treating malignant lymphomas, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma and solid tumors. Apart from cancer treatment, multispecific drugs and imaging reagents built with nanobody blocks have demonstrated their value also for detecting and tackling neurodegenerative, autoimmune, metabolic, and infectious diseases and as antidotes for toxins. In particular, multi-paratopic nanobody-based constructs have been developed recently as drugs for passive immunization against SARS-CoV-2 with the goal of impairing variant survival due to resistance to antibodies targeting single epitopes. Given the enormous research activity in the field, it can be expected that more and more multimeric nanobody molecules will undergo late clinical trials in the next future. Systematic Review Registration.

Modeling the effect of age on quantiles of the incubation period distribution of COVID-19.

BACKGROUND: The novel coronavirus SARS-CoV-2 (coronavirus disease 2019, COVID-19) has caused serious consequences on many aspects of social life throughout the world since the first case of pneumonia with unknown etiology was identified in Wuhan, Hubei province in China in December 2019. Note that the incubation period distribution is key to the prevention and control efforts of COVID-19. This study aimed to investigate the conditional distribution of the incubation period of COVID-19 given the age of infected cases and estimate its corresponding quantiles from the information of 2172 confirmed cases from 29 provinces outside Hubei in China. METHODS: We collected data on the infection dates, onset dates, and ages of the confirmed cases through February 16th, 2020. All the data were downloaded from the official websites of the health commission. As the epidemic was still ongoing at the time we collected data, the observations subject to biased sampling. To address this issue, we developed a new maximum likelihood method, which enables us to comprehensively study the effect of age on the incubation period. RESULTS: Based on the collected data, we found that the conditional quantiles of the incubation period distribution of COVID-19 vary by age. In detail, the high conditional quantiles of people in the middle age group are shorter than those of others while the low quantiles did not show the same differences. We estimated that the 0.95-th quantile related to people in the age group 23 ∼55 is less than 15 days. CONCLUSIONS: Observing that the conditional quantiles vary across age, we may take more precise measures for people of different ages. For example, we may consider carrying out an age-dependent quarantine duration in practice, rather than a uniform 14-days quarantine period. Remarkably, we may need to extend the current quarantine duration for people aged 0 ∼22 and over 55 because the related 0.95-th quantiles are much greater than 14 days.