Pharmacological considerations for next-generation protein therapeutics in cardiovascular disease.

Cardiovascular disease (CVD) remains the leading cause of death worldwide despite decades of therapeutic advances. Emerging insights into its etiology have revealed previously unappreciated cellular and molecular drivers beyond traditional risk factors, prompting the development of treatments that target newly identified culprit proteins and cells within cardiovascular tissues. Protein-based biologics-particularly monoclonal antibodies and multispecific proteins-are known for their strength and specificity in targeting and their established use as treatments for other diseases. However, extending biologics to new indications faces challenges: achieving durable effects in diseased tissues and minimizing side effects in healthy tissue. Addressing these long-standing challenges requires fine-tuning biologics' pharmacokinetic properties and pharmacodynamic effects according to target- and disease-specific requirements. In this review, we examine foundational pharmacokinetic and pharmacodynamic principles in the context of cardiovascular-targeted biologics, highlighting the role of protein design in controlling distribution, efficacy, and safety. Additionally, we discuss emerging preclinical and clinical biologics specifically designed for CVDs, as well as emerging opportunities in this landscape. These advances point toward a future where pharmacokinetics guide the rational design of next-generation protein therapeutics for CVD. SIGNIFICANCE STATEMENT: Protein-based biologics hold promise for treating cardiovascular diseases (CVD); however, their successful translation requires understanding how proteins' properties and cardiovascular physiology shape pharmacokinetic and pharmacodynamic behavior. This minireview connects foundational pharmacology principles with strategies in protein engineering suitable for CVD applications. Pharmacokinetic-guided design will accelerate the development of protein therapies that can transform CVD treatment.