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基于分子表位的抗体药物
2014-01-21 09:34 陈志南  发布范围:公开

Monoclonalantibodies (mAbs) have been widely applied in the diagnosis and treatment ofhuman diseases, such as cancer, transplant rejection, and autoimmune diseases,with inherent advantages such as specificity for target, low toxicity relativeto small-molecule drugs, long half-life in serum, and the capacity for multiplecytotoxic mechanisms of action. Therapeutic antibodies represent one of thefastest growing areas of the biopharmaceutical industry.

Upto 2009 global pharmaceutical market sales reached to 770 billion U.S. dollars,of which biotechnology drugs and genetic drugs to 130 billion U.S. dollars and 900 million U.S. dollars, respectively; among the biological drugs, antibodydrug sales was amount of more than 30 billion U.S. dollars.

Over 42 mAbs have thus far been approved by the U.S. Food and Drug Administrationand European Medicines Agency, and 16 mAbs have been approved by the State Foodand Drug Administration (SFDA) in China for therapeutic applications,particularly for cancers and autoimmune disease. One mode of cancer treatmentcurrently being investigated involves using mAbs that bind specifically totumor-associated antigens and induce an immunological response against thetargeted cancer cell.

Biomacromolecule,esp. cluster of differentiation protein as the target of therapeutic antibody,always owns many epitopes, also known as antigenic determinants, which havedifferent functions corresponding to different epitopes, and can be recognizedby the immune system, specifically by antibodies, B cells, or T cells. Ideally,the epitope(s) targeted by an antibody should be identified and characterized,thereby establishing antibody reactivity, highlighting possiblecross-reactivities, and perhaps even warning against unwanted (e.g. autoimmune)reactivities.

Althoughnew technologies for the production of mAbs have been rapidly emerging inrecent years—such as phage antibody libraries, transgenic mouse technology, andthe human memory B cell sorting technology—most of the mAbs used today wereoriginally prepared using traditional mouse hybridoma technology.

HAb18G/CD147(abbr. CD147), a novel tumor-associated antigen, had been discovered andsuccessfully developed as a target for antibody-based immunotherapy in our lab.Recent years, three epitopes were validated by resolving the antigen-antibodycomplex(HAb18G/CD147-HAb18, -5A12 and -6H8) crystal structure accordingly. Theseepitopes play different roles in inducing cancer cell metastasis and invasion,T cell activation and pathogenic infection.

Amongthese antibody pipeline, the HAb18 (IgG1) mAb was developed in our laboratoryabout 20 years ago using hybridoma technology. Its antigen, HAb18G, wasidentified by panning a hepatocellular carcinoma (HCC) cDNA expression library.A Blast search of GenBank using the HAb18G gene sequence found it homologous tothe CD147 gene (Emmprin, basigin). Thus HAb18G was named HAb18G/CD147 and nowis known as a new member of the CD147 family, which belongs to theimmunoglobulin superfamily (Protein Data Bank ID: 3B5H). Because the HAb18 mAbcan bind to HCC cells with high affinity, we created LICARTINTM [Generic name:Iodine (131I) metuximab injection], an 131I-labeled HAb18 F(ab’)2, as aradioimmunotherapeutical agent capable of targeting tumors. LICARTINTM has beenproven in clinical trials to be a safe and effective agent for HCC treatment.

1. For cancer, the epitope of CD147-HAb18

1)DNA methylation level of CD147 promoter region significatlydecrease in tumor cells;

2)Transcriptome sequencing discovered that CD147 exits differentialexpression and tissue beside cancer;

3)Identification of CD147 transcriptional splicing variants,HAb18G/CD147 belongs to Basigin-2;

4)CD147 glycosylation modification affects its biological funtion,this molecule has a specific fucose N-linked Glycan profiling;

5)CD147 contributes to the formation of EMT through TGF-β1-Slugsignaling pathway;

6)Interacted with annexin II, CD147 promotes the formation oflamellipodia and mesenchymal movement;

7)CD147 inhibits ERS-induced HCC cell apoptosis and decreaseschemosensitivity by inducing Bip expression;

8)CD147 promotes liver fibrosis via activating hepatic stellatecells;

9)CD147, a universal cancer-associated biomarker, has been found tobe highly expressed in epithelium malignant cancers

2. For auto-immune disease, the epitope of CD147-5A12

1)CD147 was be considered as a T cell activation-associated moleculewhich expression up-regulated on both activated CD4+ and CD8+ T cells;

2)Anti-CD147 mAb 5A12 inhibited T cells proliferation, dispersed theformation of the immunological synapse, decreased intracellular calciummobilization levels;

3)CD147 act as a co-stimulatory receptor to negatively regulate Tcell activation

3. For pathogenic infection, the epitope of CD147-6H8

1)Anti-CD147 mAb 6H8 inhibited theinvisionof PlasmodiumFalciparum tohuman blood cell

2)CD147 plays a functional role in invasion of SARS virus to hostcell;

3)CD147 might act as a receptor for the invasion of other pathogenicorganism

Inconclusion, HAb18G ⁄ CD147 is significantly expressed in various cancers andappears to have prognostic significance, rendering it a possiblecancer-associated biomarker for pathological diagnosis, prognostic evaluation,targeted therapy and radioimmunoimaging of a broad range of cancer types.

Thedifferent epitopes of CD147, as a cancer-associated biomarker, co-stimulatoryreceptor to negatively regulate T cell activation and a invision receptorparticipated in some pathogenic organism, will exert great impact on translationalmedicine.

TherapeuticAntibody Drugs Based on Targeted Molecular Epitopeswill be an excellentoption for treating cancers, infectious diseases, and inflammatory diseases.

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