New Modes of Antibody Drug Coupling—PDC, AOC, ABC, AAC, ISAC

In recent years, antibody drugs have undergone explosive development and occupied an increasing proportion in the market of drugs. The high specific affinity of monoclonal antibody against tumor cell antigen making it an ideal carrier for targeted drug delivery, which can be used to target chemotherapy or other drugs to tumor lesions. The existing antibody drugs have limited anti-tumor efficacy, and most patients who initially receive effective antibody therapy are prone to drug resistance. Therefore, various combined strategies are adopted. Antibody fragments-drug conjugate—FDCrnAntibody-drug conjugate (ADC) ushers in an era of explosive development. In the past 20 years, 8 ADC drugs have been approved. Last year alone, the FDA approved three ADC drugs for a record-breaking succession. Biotech companies such as Creative Biolabs are committed to the development of antibody fragment-drug conjugates (FDCs: https://www.creative-biolabs.com/adc/fragment-drug-conjugates-development.htm) to overcome the limitations of ADCs. Unlike intact monoclonal antibodies (mAbs) used in ADCs, FDC composes an antibody fragment coupled with the cytotoxic drug. The smaller molecular weight of an antibody fragment provides better tumor penetration to FDC. In addition, the shorter half-life of FDC than that of ADC enables reduced exposure in normal tissues, so that the side effects of FDC can be better controlled. Antibody fragments can be conjugated to a variety of cytotoxic drugs, and the cytotoxic load that they can achieve is much higher than that of mAbs. Antibody-oligonucleotide conjugate—AOCrnOligonucleotides have made significant progress in targeting liver cells/tissues, and a variety of products targeting liver cells expressing genes have been approved for marketing or are in late-stage clinical development. However, oligonucleotide drugs have long faced obstacles to targeted delivery, which are mostly limited to tissues that can be administered locally, such as the eye. In addition, oligonucleotides also have dose, concentration, and time dependence. In AOC, the antibody binds to the surface receptor on the target cell, which is then internalized and the oligonucleotide is released to play its role. Immune stimulating antibody conjugate—ISACrnAt present, toll-like receptor (TLR) agonists are also one of the potential tumor immunotherapies. Targeting TLR can reactivate the immune system and is also conducive to combined therapy. However, it is mostly limited to intratumoral administration because of its serious toxicity when administered systemically, which will activate non-specific immune responses, and in severe cases, may trigger a fatal cytokine storm. Therefore, the clinical development and application of TLR agonists are highly limited. Bolt Biotherapeutics solves the barriers of systemic administration of immunostimulants by coupling immunostimulants with antibodies. Previously, the company stated that it is demonstrated in animal models that this new therapy can transform immunological "cold tumors" into "hot tumors", and eliminate tumors after systemic administration, and shows good tolerance. Antibody biopolymer conjugate—ABCrnAMD (age-related macular degeneration) is the next blue ocean in the field of ophthalmology, with a large population of patients. At present, anti-VEGF drugs occupy a considerable proportion in the ophthalmology market, which, however, usually need to be administered intravitreally and have a short half-life in the vitreous, so patient compliance is low. Kodiak developed KSI-301, a new type of anti-VEGF biological agent based on the proprietary ABC technology platform. By coupling biopolymers with antibodies, the duration of the drug in the eye is prolonged, improving the efficacy and reducing the injection frequency. Antibody-antibiotic conjugate—AACrnAt present, as most antibiotics have low killing efficiency against extracellular pathogens, some researchers proposed specific treatment strategies for intracellular pathogens to promote the therapeutic effect. As early as 2015, Lehar's team first proposed and evaluated the antibody-antibiotic conjugate (AAC), which designed an anti-β-GlcNAC WTA (carbohydrate molecule on the surface of Staphylococcus aureus) antibody that can bind to free Staphylococcus aureus, and then it enters the phagocytes through Fc-mediated opsonization, and then the rifampicin antibiotics are released and kill the Staphylococcus aureus hidden in the phagocytes. In mouse disease models, AAC drugs and vancomycin were given 24 hours after infection, of which the results showed that AAC drugs can better eliminate Staphylococcus aureus.