Discussion on Antibody-based Scaffold Protein Drug Development v1
Authors: Wind Susan 
Published: June 2019

Kunitz domain The active domain of a protein molecule that inhibits the function of a protein-degrading enzyme, or a protease inhibitor, usually consists of a 50-60 amino acid-rich alpha-beta folding domain with a molecular weight of about 6 kDa. Common Kunitz-type protease inhibitors are aprotinin (bovine pancreatic trypsin inhibitor, BPTI), Alzheimer's disease amyloid precursor (APP) and TFPI. To date, only one class of antibody-based stent drug Kalbitor has been approved for marketing and belongs to the Kunitz dvd domaincategory. Ecallantide was developed by Dyax and was approved by the US FDA on November 27, 2009 under the trade name Kalbitor. Ecallantide is a plasma kallikrein inhibitor that binds to plasma kallikrein and blocks its binding site, thereby inhibiting the conversion of HMW kinin to bradykinin. This medicine is used to treat hereditary angioedema in patients 12 years of age and older. Kalbitor is a subcutaneous injection containing 10 mg/mL ecallantide per bottle. The recommended dose is 30 mg each time, in three injections. Adnectin A new class of antibody-like drugs originally designed from 10Fn3 (the 10th fibronectin type III domain dvd). Adnectin members are similar to antibody variable domainin that they consist of a sandwich structure composed of β-sheets and different Loop regions, but their sequences are altered compared to antibodies, and there is only one smaller disulfide-free bond. Thus, the tightness and specificity of Adnectin binding to the target is comparable to that of the antibody, but it is easier to genetically engineer and use a bacterial expression system for large-scale industrial production. The Adnectin molecules screened by in vitro evolution such as mRNA display, phage display and yeast display can have a dissociation constant as low as Namo or Pimo. BMS-962476 is a BMS original researcher and is an Adnectin inhibitor of PCSK9, which acts on another non-antibody pathway. BMS-962476 has a molecular weight of approximately 11.3 kDa and consists of 103 amino acid residues and is coupled to a PEG molecule. Studies of the first PCSK9 Adnectin inhibitor showed that it rapidly reduced plasma levels of PCSK9 and LDL-C, and that Adnectin-mediated inhibition was well tolerated. The drug is currently in Phase I clinical trials for the treatment of hypercholesterolemia and atherosclerosis. Angiocept Also known as Pegdinetanib, it consists of 94 amino acid residues; Cys at position 93 carries two PEG molecules by chemical modification, resulting in an overall molecular weight of about 40 kDa. The main mechanism of action of this drug is a selective inhibitor of VEGFR-2, which is used to organize tumor angiogenesis. In October 2007, the drug carried out a phase II clinical study of glioblastoma; in August 2012, the drug developed a phase II clinical study of non-small cell lung cancer and colorectal cancer. Affibodies This drug is a new class of affinity ligands consisting of 58 amino acid residues with a relative molecular mass of about 6.5 kDa. The structure contains three α-helices, which function similarly to antibodies but have some antibodies. It is called "artificial antibody" because of its properties such as low relative molecular mass, fast folding rate, high selectivity and affinity, and structural stability, which can withstand chemical modification. The Affibody molecule was originally derived from the B-segment of the immunoglobulin binding region of staphylococcal protein A. In order to improve its chemical stability, the 29th glycine in the B segment was mutated to alanine, and it has been reported as having One of the fastest protein folding rate proteins. In recent years, affibody molecules have been widely used in many fields of biological sciences, such as imaging diagnosis, therapeutics, and drug carriers. Affibodies are small enough to penetrate into tumor cells and bind to target proteins, making them ideal for cancer imaging diagnostics. The company is currently developing two types of Affibodies for tumor diagnosis, ABY-25, targeting HER2 for breast cancer diagnosis, and will enter phase III clinical phase in the fall of 2017; another molecular target EGFR to brain tumor tissue is used to help the surgeon determine the boundaries of the tumor tissue. In addition, Affibody is shifting its research and development focus to other therapeutic applications, such as drugs for psoriasis, Alzheimer's disease and autoimmune diseases. The drug ABY-035 for psoriasis treatment research will begin clinical phase II trials this fall.