Rational engineering of antibody therapeutics targeting multiple oncogene pathways

Monoclonal antibodies have significantly advanced our ability to treat cancer, yet clinical studies have shown that many patients do not adequately respond to monospecific therapy. This is in part due to the multifactorial nature of the disease, where tumors rely on multiple and often redundant pathways for proliferation. Bi- or multi-specific antibodies capable of blocking multiple growth and survival pathways at once have a potential to better meet the challenge of blocking cancer growth, and indeed many of them are advancing in clinical development.1 However, bispecific antibodies present significant design challenges mostly due to the increased number of variables to consider. In this perspective we describe an innovative integrated approach to the discovery of bispecific antibodies with optimal molecular properties, such as affinity, avidity, molecular format and stability. This approach combines simulations of potential inhibitors using mechanistic models of the disease-relevant biological system to reveal optimal inhibitor characteristics with antibody engineering techniques that yield manufacturable therapeutics with robust pharmaceutical properties. We illustrate how challenges of meeting the optimal design criteria and chemistry, manufacturing and control concerns can be addressed simultaneously in the context of an accelerated therapeutic design cycle. Finally, to demonstrate how this rational approach can be applied, we present a case study where the insights from mechanistic modeling were used to guide the engineering of an IgG-like bispecific antibody

Smoothened, Stem Cell Maintenance and Brain Diseases

International audienceThe Smoothened (Smo) receptor is a key transducer of the Sonic Hedgehog (Shh) signaling pathway in the brain. Recent studies in rodents have highlighted its major role in the maintenance of neural stem and progenitor cells in the two main neurogenic niches of the adult brain: the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus in the hippocampus. Smo may also regulate brain responses to various injuries, and its modulation in the primary cilia of brain cells is essential for regulating Shh signals. Recent clinical trials have underlined the therapeutic value of some Smo antagonists for the treatment of Hedgehog-linked medulloblastomas. Here, we review recent findings on the roles of Smo in the adult brain, and unravel research on the clinical implications for the treatment of brain diseases, that are increasingly under investigation