Cancer Therapy with Radiolabeled and Drug/Toxin-conjugated Antibodies www.tcrt.orgRadioimmunotherapy and antibody-directed chemotherapy have emerged as cancer treatment modalities with the regulatory approval of products for non-Hodgkin's lymphoma and acute myeloid leukemia. Antibody-toxin therapy is likewise on the verge of clinical fruition. Accumulating evidence suggests that radioimmunotherapy may have the best impact in minimal-disease and adjuvant settings, especially with radioresistant solid tumors. For the latter, ongoing efforts in 'pretargeting' to increase deliverable tumor radiation dose, combination therapies, and locoregional applications are also of importance. Antibody-drug conjugates have the potential to increase the therapeutic index of chemotherapy by minimizing systemic toxicity and improving tumor targeting. The design of optimal drug conjugates in this regard is predicated upon the proper choice of the target antigen, the cleavable-linker, and the drug. In respect of antibody-toxin conjugates, considerable progress has been made in chemical and recombinant immunotoxin designs, and in the advancement of many products to clinical trials. Continued development of antibody-directed therapies should expand the options available for the management of cancer.Keywords: Antibody-drug conjugates; Immunotoxins; Hematologic cancers; Monoclonal antibody; Radioimmunotherapy; Review; and Solid cancers.
IntroductionMonoclonal antibody (MAb)-directed cancer therapy has evolved in the past 3 decades into an emerging modality in clinical practice. The regulatory approvals for several of the MAb products, either in unmodified forms or as carriers of anticancer therapeutics, have created an impetus for the ongoing development of newer products and newer treatment paradigms for targeted therapy. Significant clinical impact has been documented with naked antibody products, such as rituximab (Rituxan®; Biogen Idec), trastuzumab (Herceptin®; Genentech), cetuximab (Erbitux®; ImClone), and bevacizumab (Avastin®; Genentech), used alone or in combination with other modalities. This review's focus, however, is on recent developments in MAbs used as vehicles for tumoricidal radionuclides, drugs, and protein toxins. Abbreviations: AcBut, 4-(4-acetylphenoxy)butanoic acid; bsAb, Bispecific antibody; CD, cluster designation; CEA, Carcinoembryonic antigen; DOTA, 1,4,7,N',N'',tetraacetic acid; DTPA, Diethylenetriaminepentaacetic acid; Dox, Doxorubicin; Gy, Gray; IC 50 , 50% inhibitory concentration; IL-2, Interleukin-2; LET, Linear energy transfer; MAb, Monoclonal antibody; MHC, Major histocompatibility complex; MTD, Maximum tolerated dose; NHL, Non-Hodgkin's lymphoma; PEG, Polyethylene glycol; RAIT, Radioimmunotherapy; RNase, Ribonuclease; sAv, streptavidin; SCID, Severe combined immunodeficient.'crossfire' effect of irradiation of non-targeted tumor cells means that every cell need not be targeted to be sterilized. In addition, there is no specific requirement for antibody to internalize upon binding to its antigen. Drug/t...