Padlock Therapeutics was a biotechnology company headquartered in Cambridge, Massachusetts, focused on the discovery and development of new medicines. The company’s primary mission centered on addressing destructive autoimmune diseases through innovative drug discovery. This involved exploring novel therapeutic approaches to potentially transform the lives of patients suffering from these conditions.
Understanding PADs and Citrullination
Padlock Therapeutics’ scientific approach was rooted in targeting protein arginine deiminases (PADs), a unique family of enzymes. These enzymes are responsible for catalyzing a specific post-translational modification known as citrullination. During citrullination, PADs convert peptidyl-arginine residues within proteins into peptidyl-citrulline.
The modification by PADs impacts protein structure and function, influencing various biological processes. Citrullination can affect the interaction of proteins with DNA, thereby influencing gene expression. Dysregulation or overexpression of PADs, leading to increased protein citrullination, has been observed in various disease states. This aberrant activity can contribute to the development and progression of autoimmune conditions by altering proteins, potentially leading to them being recognized as foreign by the body’s immune system.
Diseases Targeted by PAD Inhibition
Padlock Therapeutics aimed to address a range of diseases where PAD activity and citrullination are implicated in pathology. These included prominent autoimmune disorders such as rheumatoid arthritis, multiple sclerosis, and lupus. In rheumatoid arthritis, increased levels of citrullinated proteins and anti-citrullinated protein antibodies are common and correlate with disease severity and joint damage. PADs, particularly PAD2 and PAD4, show increased expression and activity in the inflamed joints of rheumatoid arthritis patients.
Beyond autoimmune conditions, the company also explored the role of PADs in neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease, as well as various cancers. In these conditions, excessive protein citrullination may contribute to the inflammatory responses or other pathological mechanisms. The therapeutic strategy of PAD inhibition seeks to prevent the progression of these conditions by blocking the formation of autoantigens, which are proteins that mistakenly trigger an immune response against the body’s own tissues. This approach aims to intervene early in the disease process, potentially preventing disease development and associated tissue destruction.
The Acquisition and Future of PAD Inhibitors
Padlock Therapeutics was acquired by Bristol-Myers Squibb (BMS) in March 2016. The acquisition was driven by BMS’s interest in Padlock’s Protein/Peptidyl Arginine Deiminase (PAD) inhibitor discovery program. This program was seen as a potentially transformative approach for treating rheumatoid arthritis and other autoimmune diseases, including systemic lupus erythematosus. The transaction included upfront and near-term contingent milestone payments of up to $225 million, with additional contingent consideration of up to $375 million based on the achievement of specific development and regulatory milestones.
The acquisition by BMS underscored the growing recognition of PAD inhibition as a promising therapeutic strategy. By targeting PAD enzymes, researchers aim to eliminate the antigens that drive autoimmunity, potentially with a limited impact on the broader immune system. This approach continues to hold significance in the field of autoimmune disease research, offering a pathway to prevent disease progression and potentially induce long-term remission in patients. The ongoing research into PAD inhibitors, even after Padlock Therapeutics’ acquisition, highlights their potential in addressing a range of inflammatory and autoimmune conditions.