The Dawn of a New Era: Targeting the “Undruggables” with Antibody-Based Therapeutics

Abstract

The high selectivity and affinity of antibodies toward their antigens have made them a highly valuable tool in disease therapy, diagnosis, and basic research. A plethora of chemical and genetic approaches have been devised to make antibodies accessible to more “undruggable” targets and equipped with new functions of illustrating or regulating biological processes more precisely. In this Review, in addition to introducing how naked antibodies and various antibody conjugates (such as antibody-drug conjugates, antibody-oligonucleotide conjugates, antibody-enzyme conjugates, etc.) work in therapeutic applications, special attention has been paid to how chemistry tools have helped to optimize the therapeutic outcome (i.e., with enhanced efficacy and reduced side effects) or facilitate the multifunctionalization of antibodies, with a focus on emerging fields such as targeted protein degradation, real-time live-cell imaging, catalytic labeling or decaging with spatiotemporal control as well as the engagement of antibodies inside cells. With advances in modern chemistry and biotechnology, well-designed antibodies and their derivatives via size miniaturization or multifunctionalization together with efficient delivery systems have emerged, which have gradually improved our understanding of important biological processes and paved the way to pursue novel targets for potential treatments of various diseases.

Genetically Encoded Photocatalysis Enables Spatially Restricted Optochemical Modulation of Neurons in Live Mice

“…In contrast, the photocatalytic methods only activate small molecules that are spatially proximal to the excited photocatalysts (Figure B). , With the μMap method for proximal protein labeling, antibody-tagged iridium photocatalysts provide selective cell-membrane microenvironment mapping for cancer and immune cells. − These photocatalytic reactions generate concentration gradients of reactive species radiating from the photocatalyst to provide spatial specificity. While effective, those methods were unsuitable for neuronal modulations due to the neuronal toxicity from heavy-metal photocatalysts and the poor neuronal specificity from antibody targeting. , To achieve neuronal modulation with photocatalysis, key bottlenecks need to be conquered: i ) The photocatalysis needs to be compatible with neurons, especially the compatibility of the ultrasensitive neurons to the unavoidable reactive oxygen species generation by photosensitization; ii ) the photocatalytically generated uncaged small molecules need to provide spatial specificity as desired compared to photolytic uncaging; and iii ) the metal-free photocatalysts in neurons need to uncage small molecules with efficiency comparable to that of heavy-metal photocatalysts. Herein, we report the first genetically encoded metal-free photocatalysis method to modulate neurons with small molecules after overcoming the above challenges (Figure C).…”

Amplification-Free Ratiometric Electrochemical Aptasensor for Point-of-Care Detection of Therapeutic Monoclonal Antibodies

“…As a class of innovative biopharmaceutical products and among the best-selling drugs, therapeutic monoclonal antibodies (mAbs) exhibit the advantages of exquisite specificity, low side effects, long serum half-life, and high therapy efficacy . With benefits from the in-depth understanding of the molecular biological mechanisms of disease evolution and the continuous emergence of new targets, therapeutic mAbs have found widespread application in the immunotherapy of human diseases, such as tumors, neurological diseases (e.g., Alzheimer’s disease), autoimmune diseases (e.g., rheumatoid arthritis), cardiovascular diseases, and infectious diseases (e.g., COVID-19) .…”

“…A s a class of innovative biopharmaceutical products and among the best-selling drugs, therapeutic monoclonal antibodies (mAbs) exhibit the advantages of exquisite specificity, low side effects, long serum half-life, and high therapy efficacy. 1 With benefits from the in-depth understanding of the molecular biological mechanisms of disease evolution and the continuous emergence of new targets, therapeutic mAbs have found widespread application in the immunotherapy of human diseases, such as tumors, 2 neurological diseases (e.g., Alzheimer's disease), 3 autoimmune diseases (e.g., rheumatoid arthritis), 4 cardiovascular diseases, 5 and infectious diseases (e.g., COVID-19). 6 For example, therapeutic mAbs, like rituximab (a chimeric mAb against the protein CD20), trastuzumab (a humanized mAb against the human epidermal growth factor receptor 2 (HER2)), bevacizumab (a humanized mAb against the vascular endothelial growth factor (VEGF)), and panitumumab (a humanized mAb against the epidermal growth factor receptor (EGFR)), have been officially approved for the clinical use in the therapy of diverse tumors, such as acute myeloid leukemia, lung cancer, colorectal cancer, breast cancer, glioblastoma, and stomach cancer.…”

Bispecific Antibodies Produced via Chemical Site-Specific Conjugation Technology: AJICAP Second-Generation

“…Bispecific antibodies (BisAbs) are genetically engineered antibodies that simultaneously bind to two different epitopes. Currently, there are more than 100 BisAb formats. , Their dual specificity allows BisAbs to be used in a broad range of applications. BisAbs are used to redirect effector cells, which enables them to deliver T cells, natural killer (NK) cells, and other cells directly to tumor cells.…”