Targeted Biologics: The New Frontier for Precision Therapy

Functionalized antibodies, protein subs titution, supplementation therapies, and enzyme-based therapeutics areprotein-based approaches for the treatment and cure of human genetic and acquired diseases. Gene editing andRNA-based therapeutics, including siR NAs, microRNAs, and antisense oligonuc leotides (ASOs), target the ma-chinery that produces disease-associat ed proteins. Protein-based and RNA-based products are collectively referredto as biologics. This Thematic Issue opens a novel specialized s ection of Current Medicinal Chemistry focused ontargeted biologics at various stages of discovery, preclinical and clinical development. We hope it might encouragethe advancement of this field by stimulating researchers to share their results.Within this issue, readers will find papers discussing th e use of replacement proteins therapeutics, with two ex-amples provided. Alpha-1-antitrypsin and C-1 inhibitor (or C1-esterase inhibitor) both belong to the family of ser-pins and are indicated for the treatment of conditions that result from pat hologically low levels or non-functionalvariants. Alpha-1-antitrypsin is a small protein that inhib its the catalytic action of el astase, a proteolytic enzyme.When the action of elastase is not properly counterbalan ced by alpha-1-antitrypsin in the lung, pulmonary emphy-sema develops. Alpha-1-antitrypsin was approved more than thirty years ago and is used for the treatment of Alpha-1-antitrypsin deficiency. The paper by Bianchera et al. [1] reports on issues associated with alpha-1-antitrypsin pro-duction from either animal sources or heterologous expre ssion, focusing on existing and novel protein formulationsand delivery strategies.The C-1 inhibitor is involved in a re gulatory network of comple ment, contact, coagulation, fibrinolytic systemsand functions as an anti-inflammatory agent in circulation. C-1 inhibitor is used as a prophylactic or acute treatmentin Hereditary Angioedema (HAE), which is a rare genetic disease. The paper by Karnaukhova et al. [4] provides anoverview of the biochemical properties of C-1 inhibitor, its role in HAE, recent progress in therapeutic strategies forthis disease treatment, as well as potential applications fo r sepsis, endotoxin shock, antibody-mediated rejection fol-lowing kidney transplantation, and severe systemic abnormalities related to COVID-19.During the Vietnam War in the late 1960s, the United States started searching for blood substitutes, such as mod-ified hemoglobin or perfluorocarbon solutions, to replace transfusions when blood was unavailable. Since then,many attempts have been carried out, including the devel opment of chemically and/or genetically modified hemo-globins designed to mimic red blood cells. The paper by Sakai et al. [7] summarizes the intense activities carriedout predominantly in Japan towards th e development of hemoglobi n-containing liposomes. Issues associated withlipids purity, hemoglobin purification, and stability towards oxidation are presented and discussed.There are many pathophysiologic aberrati ons associated with genetic variants of hemoglobin, often caused bysingle amino acid substitutions. One such example is the single amino acid Glu-Val substitution at position 6 of thebeta chains, leading to sickle cell disease. Hydroxyurea is a mainstay of sickle cell disease therapy to increase thepercentage of fetal hemoglobin. Novel marketed therap eutics are based on compounds either interacting directlywith hemoglobin to modulate oxygen binding or altering water-controlling pump systems. Alternative and morerecently proposed approaches are based on hematopoietic st em cell transplantation and gene therapy platforms.These approaches are reviewed by Garg et al. [3] which discuss advances in precision therapy for sickle cell diseaseand the preclinical and clinical advances in autologous hematopoietic stem cell gene therapy.Breathing is a fundamental function for all living systems. It is made possible in both animals and humans by thepresence of pulmonary surfactant, a complex mixture of lipids and proteins secreted into the alveolar lumen. Its roleis the maintenance of lung homeostasis to avoid alveolar collapse. In addition, pulmonary surfactant provides a bar-rier against inhaled pathogens. An insufficient amount of su rfactant or its functional inac tivation is associated withlung pathologies, including neonatal resp iratory distress syndrome. Pioselli et al. [6] reviewed the current state ofpulmonary surfactant mimetics in development for replacement therapy. Presently, there are lifesaving products inthis class approved for worldwide use in premature infants. Because novel proteins being studied in developmentalstages are typically extracted from porcine sources, the pr oduction strategies for tailored surfactant proteins by re-combinant technologies are being refined. Further, pulmonary surfactants ar e attractive candidates for synergisticand carrier molecules that enhance the treatment of a variety of respiratory diseases.Enzymes are biomolecules that catalyze an impressive variety of chemical reactions. A key feature of an enzymeis its specificity for specific substrates. Therefore, it is not surprising that enzymes have been attractive for carryingout selective therapeutic actions. There are two main medicinal strategies based on enzymes: i) supplementation andii) replacement. Cioni et al. [2] focused on a range of disorders wher e the supplementation of enzymes to patientsprovides the basis for therapeutic interventions, including clotting disorders, cystic fibrosis, lactose intolerance, col-lagen-based disorders, and cancers. Enzymes for therapeutic indications are increasing as a result of advancementsin genetic engineering techniques. Typi cal examples are asparaginase and methionine gamma-lyase, used in cancertherapy to degrade either asparagine or methionine, respec tively. The rationale is based on the vital need for theseamino acids by cancer cells. Depletion of these amino acids in the cellular environment slows or prevents cancercell growth, potentiating the efficacy of traditional chemotherapies. Because enzymes are very "fragile" biomole-cules, novel strategies are being employed to optimize their stability and delivery. Enzyme replacement therapy isalso the focus of the paper by Marchetti et al. [5]. Genetic deficiencies of a specific enzyme can lead to the accumu-lation of its substrates and toxic effect s. For example, Gaucher and Fabry diseases are the first rare genetic lysoso-mal storage disorders for the treatment of which enzymes were successfully delivered. In these examples, enzymeswere initially obtained from animal sources, then produced using recombinant technology with chemical modifica-tions or genetic variants to enhance and extend their activity.This first issue of the Targeted Biologics represents a small sampling of successful applications of biologics. Weare confident that Current Medicinal Chemistry readers will find these examples intellectually stimulating and allowthe journal to advance exciting concepts in Biologics for targeted therapy.