Cancer Radioimmunotherapy

Abstract

Targeting of radionuclides with antibodies, or radioimmunotherapy, has been an active field of research spanning nearly 50 years, evolving with advancing technologies in molecular biology and chemistry, and with many important preclinical and clinical studies illustrating the benefits, but also the challenges, which all forms of targeted therapies face. There are currently two radiolabeled antibodies approved for the treatment of non-Hodgkin lymphoma, but radioimmunotherapy of solid tumors remains a challenge. Novel antibody constructs, focusing on treatment of localized and minimal disease, and pretargeting are all promising new approaches that are currently under investigation.

Selective killing of Kaposi's sarcoma-associated herpesvirus lytically infected cells with a recombinant immunotoxin targeting the viral gpK8.1A envelope glycoprotein

“…This concept, which has been vigorously pursued for decades in the oncology field, exploits three variations of the theme of targeted cytotoxic proteins: 36 (1) antibody-drug conjugates (ADCs) in which mAbs are chemically coupled to low molecular weight cytotoxic compounds, 37,38 (2) radioimmunotherapy whereby radionuclide-conjugated mAbs deliver lethal doses of radiation to the targeted cells, 39,40 and (3) immunotoxins wherein the antigen-binding regions of mAbs are linked (chemically or genetically) to the effector domains of protein toxins typically of bacterial or plant origin. 41,42 The targeted cytotoxic protein approach is receiving increasing attention Complementation of anti-KSHV activity by inhibition of viral DNA replication and targeted killing of infected cells.…”

“…37,38,84 Two radioimmunotherapeutic proteins, ibritumomab tiuxetan (Zevalin ® ) and tositumomab-I131 (Bexxar ® ) are FDA-approved for treatment of certain types of lymphoma; several other radionuclide-conjugated antibodies are advancing in the clinical pipeline. 39,40 In making general comparisons of these approaches, immunotoxins have the disadvantages of relatively short plasma half pTK21.8, 92 previously subjected to sequential single digestion with NdeI (polished with T4 Klenow fragment to generate a blunt end) and HindIII and alkaline-phosphatase treated. The resulting clone was named as 2014-PE38.…”

A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

“…Besides supporting development and strengthening of the adaptive immunity, therapeutic antibodies are able to trigger early anti-tumor events such as receptor blockade, cytostasis, apoptosis, complement-dependent cytotoxicity and/or antibody-dependent cytotoxicity [397][398][399]. Bispecific antibodies are used to mount and sustain tumor-specific cellular responses or in radioimmunotherapy to improve target binding, selectivity, and efficacy [400][401][402][403]. A widely studied target is the cytotoxic T-lymphocyteassociated antigen CTLA-4, also called CD152, which regulates T-cell activation.…”

Emerging Trends for Radioimmunotherapy in Solid Tumors

“…2 Several articles have reviewed various other aspects of solid tumor RIT, including the role of radiobiology in tumor cell killing, clinical experience with RIT, pretargeting strategies, targeted therapies, optimization of delivery, and the use of various radionuclides for RIT. [3][4][5][6][7][8][9][10][11][12][13] Development of efficient labeling methodologies has fueled recent interest in exploiting short-range, high energy a-particle emitting radionuclides for treating solid tumors by RIT in a minimal residual disease setting. In addition to the identification and use of new antigenic targets, RIT and radioimmunoimaging strategies are also being developed using monoclonal antibodies (MAbs) that are conventionally approved as unlabeled therapeutic agents.…”