ABSTRACT
Leveraging the specificity of antibody to deliver cytotoxic agent into tumor, antibody-drug conjugates (ADCs) have become one of the hotspots in the development of anticancer therapies. Although significant progress has been achieved, there remain challenges to overcome, including limited penetration into solid tumors and potential immunogenicity. Fully human single-domain antibodies (UdAbs), with their small size and human nature, represent a promising approach for addressing these challenges. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a glycosylated cell surface protein that rarely expressed in normal adult tissues but overexpressed in diverse cancers, taking part in tumorigenesis, progression, and metastasis. In this study, we investigated the therapeutic potential of UdADC targeting CEACAM5. We performed biopanning in our library and obtained an antibody candidate B9, which bound potently and specifically to CEACAM5 protein (KD = 4.84 nM) and possessed excellent biophysical properties (low aggregation tendency, high homogeneity, and thermal stability). The conjugation of B9 with a potent cytotoxic agent, monomethyl auristatin E (MMAE), exhibited superior antitumor efficacy against CEACAM5-expressing human gastric cancer cell line MKN-45, human pancreatic carcinoma cell line BxPC-3 and human colorectal cancer cell line LS174T with IC50 values of 38.14, 25.60, and 101.4 nM, respectively. In BxPC-3 and MKN-45 xenograft mice, administration of UdADC B9-MMAE (5 mg/kg, i.v.) every 2 days for 4 times markedly inhibited the tumor growth without significant change in body weight. This study may have significant implications for the design of next-generation ADCs.
Subject(s)
Antineoplastic Agents , Immunoconjugates , Single-Domain Antibodies , Humans , Animals , Mice , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic use , Cell Adhesion Molecules , Cytotoxins , Xenograft Model Antitumor Assays , Carcinoembryonic Antigen , GPI-Linked ProteinsABSTRACT
There are few articles or reports collecting evidence about Kudiezi injection from premarketing and postmarketing research or studies systematically. This article is an exact miniature of a systematical report about Kudiezi injection. We analyzed information from four aspects, such as quality control reports, non-clinical premarketing safety experiments, postmarketing research (efficacy studies, hospital information system data and national spontaneous reporting system data), and literature analysis. All the four aspects build an evidence body for Kudiezi injection in order to inform its safety use in clinical practice and further study.
Subject(s)
Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/adverse effects , Hospital Information Systems , Humans , InjectionsABSTRACT
Interleukin (IL)-33 is a member of the interleukin-1 cytokine family that is produced by many different types of tissues including the central nervous system (CNS). IL-33 mediates its effects via its heterodimeric receptor complex, comprised of ST2 and the IL-1 receptor accessory protein (IL-1RAcp). As a pleiotropic nuclear cytokine, IL-33 is a crucial factor in the development of cardiovascular diseases, allergic diseases, infectious diseases, and autoimmune diseases. Recently, accumulated evidence shows that the IL-33/ST2 axis plays a crucial and diverse role in the pathogenesis of CNS diseases, including neurodegenerative diseases, cerebrovascular diseases, infectious diseases, traumatic CNS injury, chronic pain, etc. In this review, we discuss the recent findings in the cellular signaling of IL-33 and advancement of the role of IL-33 in several CNS diseases, as well as its therapeutic potential for the treatment of those diseases.