Artificially modified IgG molecules are increasingly utilized in industrial and clinical applications. In the present study, the method of chemical conjugation by affinity peptide (CCAP) for site-specific chemical modification has been developed by using a peptide that bound with high affinity to human IgG-Fc. This method enabled a rapid modification of a specific residue (Lys248 on Fc) in a one-step reaction under mild condition to form a stable amide bond between the peptide and Fc. The monovalent peptide-IgG conjugate not only maintained complete antigen binding but also bound to Fc receptors (FcRn, FcγRI, and FcγRIIIa), indicating that it is a suitable conjugate form that can be further developed into highly functional antibody therapeutics. CCAP was applied for the preparation of an antibody-drug conjugate and a bispecific antibody to demonstrate the usefulness of this method.

Background/Aim: Adult T-cell leukemia (ATL) is a hematological malignancy caused by infection with human Tcell leukemia virus type 1 (HTLV-1). Chemotherapy, antibody therapy, and bone marrow transplantation are used to treat this disease, however, median survival time has not been significantly improved. Our aim was to develop and evaluate a novel antibody-drug conjugate (ADC) with regards to cell cytotoxicity and target specificity. Materials and Methods: In this study, we have constructed a novel ADC, which is composed of an anti-CD70 single chain Fv-Fc antibody conjugated with the anticancer agent emtansine using a novel antibody modification method. Cell cytotoxicity and target specificity were assessed using a cell proliferation assay. Results: The anti-CD70 ADC selectively killed HTLV-1-infected cells and ATL cells without affecting other cells. Conclusion:The anti-CD70 ADC offers some chemotherapeutic potential for the treatment of ATL.Adult T-cell leukemia (ATL) is a refractory hematological disorder caused by infection with human T-cell leukemia virus type 1 (HTLV-1) (1, 2). A number of HTLV-1 carriers exist in the southern part of Japan, in particular, in Kagoshima and Okinawa areas (3, 4). It is assumed that approximately one million people in Japan and more than 30 million people worldwide are infected with this virus (5). HTLV-1 infection has a long incubation period, and only 5% of the infected individuals will develop ATL during their lifetime (6). However, once developed, its prognosis is extremely poor, and it causes a variety of complications, such as lymphadenopathy, skin rash, diarrhoea, swelling of liver and spleen, and subcutaneous tumor (7, 8). Furthermore, opportunistic infections are major causes of death for ATL patients. There are 4 types of ATL in terms of clinical manifestations: i) acute, ii) lymphoma, iii) smoldering, and iv) chronic ATL (4, 9). Although various therapeutic modalities, including combination chemotherapy, antibody therapy, and bonemarrow transplantation are applied to the acute and lymphoma types of ATL, most of them have serious adverse effects or restrictions of use (10)(11)(12). Therefore, it is still mandatory to develop new treatment options for ATL.Antibody drug conjugates (ADCs) have been recently introduced as part of anticancer therapy (13-17); however, the current methods for producing an accurate number of conjugated drugs in ADCs are difficult to control (18,19). In addition, anticancer drugs sometimes diminish the antigen-binding capacity of ADCs due to their interaction with the variable region of the antibody. To circumvent this problem, the chemical conjugation by the affinity peptide (CCAP) method using an IgG-binding peptide has been developed (20). We previously reported that CD70, a ligand of the tumor necrosis factor (TNF) receptor superfamily, was highly expressed on the surface of various HTLV-1-carrying T-cell lines and of the primary CD4 + T-cells isolated from acute type ATL patients (21). Such an expression was not observed for uninfected T...

No abstract