Development of Novel PD1/PD-L1 Antagonists Using Circular Cys-Knotted Micro Proteins
Abstract
This proposal addresses the overarching challenge to develop effective treatments for patients with lung cancer. The proposed work will focus in the area of therapy to fill gaps in lung cancer treatment that may affect the general population but have a particularly profound impact on military health. This project proposes the use of a novel in-cell approach for the screening of large micro-antibody like libraries for the selection of specific compounds able to activate the patient s own immune system to destroy the lung cancer cells. Increasing evidence shows that tumors can evade adaptive immunity and disrupt immunological checkpoint pathways. The PD-1/PD-L1 pathway in cancer is implicated in tumors escaping immune destruction and is a novel, very promising therapeutic target. Tumors that express PD-L1 can often be aggressive and carry a poor prognosis. Expression of PD-L1 allows tumors to directly suppress anti-tumor cytolytic T cell activity through T-cell downregulation and inhibition. Recent clinical trials using therapeutic (monoclonal antibodies) mAbs against PD-1 or PD-L1 have shown very encouraging activity against a variety of tumors including lung cancer, in particular, non-small-cell lung cancer (NSCLC). Blocking the PD-1/PD-L1 pathway with mAbs has led to unprecedented tumor response and control in some patients with NSCLC. The use of mAbs to block the PD-1/PD-L1 pathway has also shown a good safety profile and has resulted in durable responses in a variety of cancers, including lung cancer, even after stopping treatment. Therapeutic mAbs are the fastest growing class of new therapeutic molecules. They hold great promise for the treatment of a variety of diseases, including cancer and chronic inflammatory diseases. However, the current manufacturing and purification processes cause limitations in the production capacity of therapeutic antibodies, leading to an increase in cost. For example, the annual cost associated with using infliximab (Remicade®) or adalimumab (Humira®), two anti-TNFalpha mAbs approved to treat auto-immune diseases such as Crohn s disease, is estimated to be above $110,000 per patient per year. These excessive costs highlight the need to find more cost-effective alternatives to mAbs. We propose the development of a breakthrough class of micro-protein-based drugs called cyclotides that are stable and biologically active, with good drug-like properties, including resistance to degradation, the ability to cross cell membranes and good pharmacological properties. We are currently collaborating with Bristol-Myers Squibb to explore the pharmacological applications of different bioactive cyclotides already developed at the Camarero group. This class of compounds represents a novel cost-effective solution for modulating both intracellular and extracellular protein-protein interactions, which have been identified as critical control points for most human diseases. Specifically, we propose to deploy the power of molecular evolution to enable generation and selection of cyclotides able to inhibit selectively the interaction between receptor PD-1 and its ligand PD-L1. These cyclotides should provide safe and low-cost alternatives to therapeutic monoclonal antibodies for lung cancer immunotherapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610147
Entities
People
- Julio A Camarero
Organizations
- United States Army
- University of Southern California