What Can De Novo Protein Design Bring to the Treatment of Hematological Disorders?

Abstract

Protein therapeutics have been widely used to treat hematological disorders. With the advent of de novo protein design, protein therapeutics are not limited to ameliorating natural proteins but also produce novel protein sequences, folds, and functions with shapes and functions customized to bind to the therapeutic targets. De novo protein techniques have been widely used biomedically to design novel diagnostic and therapeutic drugs, novel vaccines, and novel biological materials. In addition, de novo protein design has provided new options for treating hematological disorders. Scientists have designed protein switches called Colocalization-dependent Latching Orthogonal Cage–Key pRoteins (Co-LOCKR) that perform computations on the surface of cells. De novo designed molecules exhibit a better capacity than the currently available tyrosine kinase inhibitors in chronic myeloid leukemia therapy. De novo designed protein neoleukin-2/15 enhances chimeric antigen receptor T-cell activity. This new technique has great biomedical potential, especially in exploring new treatment methods for hematological disorders. This review discusses the development of de novo protein design and its biological applications, with emphasis on the treatment of hematological disorders.

Directed evolution of genetically encoded LYTACs for cell-mediated delivery

“…In this study, we developed a small (20 to 30 kDa), genetically encoded LYTAC that can be secreted by primary human T cells. While there are multiple approaches to engineering genetically encoded LYTACs, a major benefit of using IGF2 is that it is a human protein, which is likely to decrease its immunogenicity compared to nonhuman proteins or computationally ( 45 , 46 ) designed proteins ( 47 ). Nevertheless, the human immune system is complex and there exist mechanisms by which GELYTACs could still elicit anti-drug antibodies ( 48 ).…”

Directed Evolution of Genetically Encoded LYTACs for Cell-Mediated Delivery

“…In this study, we developed a small, genetically encoded LYTAC that can be secreted by primary human T cells. While there are multiple approaches to make a genetically encoded LYTAC, a major benefit of using IGF2 is that it is a human protein, which should decrease its immunogenicity compared to nonhuman mammalian proteins or computationally (44,45) designed proteins (46). Indeed, during our study, another paper was published that utilized a protein-based targeting chimera composed of 2 computationally designed binders to internalize EGFR via cell secretion (21), which could be immunogenic.…”