Team:Shenzhen SFLS/Background

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Background Written by Yuhe Wu.

1.1 Overview of drug delivery systems (DDS) and antibody-drug conjugates (ADCs)

Drug delivery is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals. Drug delivery systems are widely researched and developed to improve the delivery of pharmaceutical compounds and molecules. Now, research in this field focuses not only on improving oral and injectable systems, but also on additional routes of administration including pulmonary, transdermal, ocular and nasal routes. Among these DDS, we would focus on antibody-drug conjugates.
Antibody-drug conjugates (ADCs) are targeted bioconjugate pharmaceuticals that combine the benefits of monoclonal antibodies (mAbs) and cytotoxic drugs to treat cancer. ADCs potentially offer a development path for highly toxic drugs that are otherwise difficult to clinically implement due to off-target toxicity, which has an advantage over other DDSs in the field of cancer treatment. Unfortunately, the main issues that challenge successful monoclonal antibodies also limit ADCs, specifically: (i) poor access to hypoxic tumor areas and generally poor tumor penetration, (ii) issues concerning the non-target site uptake, and (iii) undesirable immune system responses via Fc interactions.

Fig.1.1.1 Structure of Antibody-drug conjugates.

1.2. Basic information about p185^her2/neu

P185her2/neu is a 185-kDa transmembrane receptor. The receptor is encoded by e c-erbB-2 gene (HER-2/neu) which is a member of the class of oncogene associated with tyrosine protein kinase. There is direct concordance between c-erbB-2 gene amplification and overexpression of the p185her2/neu protein. Since 25 years ago, p185her2/neu has been recognized that both amplification and overexpression of p185her2/neu are associated with short survival and recurrence of cancer. P185her2/neu is also recognized as an early tumor marker especially for breast and ovarian cancers.

Fig 1.2.1. Crystal structure of ErbB2 domains 1-3. (pdb2A91)

1.3. Basic information of single chain fragments variable (scFv)

A single chain fragment variable (scFv) is a recombinant protein which consists of the variable regions of both heavy and light chain from a mAb. The variable fragments are joined together with a flexible linker peptide. Numerous scFv antibodies have been constructed against hapten, protein, carbohydrate, receptor, tumor antigen and viruses. They can be easily expressed in E. coli, which allows protein engineering to improve the properties of scFv such as increase of affinity and alteration of specificity.
Fig. 1.3.1 Antibody model showing subunit composition and domain distribution along the polypeptide chains. Single-chain fragment variable (scFv) antibody generated by recombinant antibody technology appears in the shaded area.