Cheng, A. C. | Search bioRxiv

bioRxiv2020

Discovery of A New Class of Integrin Antibodies for Fibrosis

Lung fibrosis, or the scarring of the lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis is worse than most types of cancer. We previously discovered that MK-0429 is an equipotent pan-inhibitor of all v integrins that reduces proteinuria and kidney fibrosis in a preclinical model. In the present study, we further demonstrated that MK-0429 significantly inhibits fibrosis progression in a bleomycin-induced lung injury model. In search of newer integrin inhibitors for fibrosis, we characterized monoclonal antibodies discovered using Adimabs yeast display platform. We identified several potent neutralizing integrin antibodies with unique human and mouse cross-reactivity. Among these, Ab-31 blocked the binding of multiple v integrins to their ligands with IC50s comparable to those of MK-0429. Furthermore, both MK-0429 and Ab-31 suppressed integrin-mediated cell adhesion and latent TGF{beta} activation. In IPF patient lung fibroblasts, TGF{beta} treatment induced profound SMA expression in phenotypic imaging assays and Ab-31 demonstrated superior in vitro activity at inhibiting SMA expression, suggesting that the integrin antibody is able to modulate TGF{beta} action though mechanisms beyond the inhibition of latent TGF{beta} activation. Together, our results highlight the potential to develop newer integrin therapeutics for the treatment of fibrotic lung diseases. One Sentence Summarytargeting integrin in lung fibrosis

pharmacology and toxicology↗

bioRxiv2020

Capturing heterogeneous infectiousness in transmission dynamic models of tuberculosis: a compartmental modelling approach

Infectiousness heterogeneity among individuals with tuberculosis (TB) is substantial and is likely to have a significant impact on the long-term dynamics of TB and the effectiveness of interventions. However, there is a gap in capturing heterogeneous infectiousness and evaluating its impact on the effectiveness of interventions. Informed by observed distribution of secondary infections, we constructed a deterministic model of TB transmission using ordinary differential equations. The model incorporated assumption of heterogeneous infectiousness with three levels of infectivity, namely non-spreaders, low-spreaders and super-spreaders. We evaluated the effectiveness of dynamic transmission untargeted and targeted implementation of an intervention intended to represent active case finding with a point-of-care diagnostic tool. The simulated intervention detected 20% of all TB patients who would otherwise have been missed by the health system during their disease episode and was compared across four epidemiological scenarios. Our model suggested that targeting the active case finding intervention towards super-spreaders was more effective than untargeted intervention in all setting scenarios, with more effectiveness in settings with low case detection and high transmission intensity. For instance, a targeted intervention achieved a 42.2% reduction in TB incidence, while the untargeted intervention achieved only a 20.7% reduction over 20 years, given the same number of people treated. Although the most marked impact on equilibrium TB incidence came from the rate of late reactivation, the proportion of super-spreaders and their relative infectiousness had shown substantial impact. Targeting active case-finding interventions to highly infectious cases likely to be particularly beneficial in settings where case detection is poor. Heterogeneity-related parameters had an equivalent effect to several other parameters that have been established as being very important to TB transmission dynamics.

microbiology↗