New Antibody Conjugates in Cancer Therapy

Targeting of drugs, radiation and protein toxins to cancer selectively with monoclonal antibodies (MAbs) has been considerable as a topic of interest and an area of continued development. Radioimmunotherapy of lymphoma using directly labeled MAbs is of current interest after approval of two radiolabeled anti-CD20 MAbs, as illustrated with the near 100% overall response rate obtained in a recent clinical trial using an investigational radiolabeled 90Y-epratuzumab ,anti-CD22 MAb. The advantage of pre targeted RAIT over directly labeled MAbs is continuing to be validated in preclinical models of solid tumors and lymphoma. Importantly, the advantages of combining RAIT with radiation sensitizers, with immunotherapy, or a drug conjugate targeting a different antigen are being studied clinically and pre clinically. The area of drug-conjugated antibodies is progressing with encouraging data for the trastuzumab-DM1 conjugate in a phase I clinical trial in HER2-positive breast cancer. The technology of Dock-and-Lock platform has contributed to the design and the evaluation of antibody-toxin conjugates and complex antibody-cytokine.

RADIOIMMUNOCONJUGATES

Radioimmunotherapy (RAIT) involves in the application of radiolabeled MAbs for targeted radiotherapy (RT). Both directly radiolabeled MAbs and in vivo radiolabelings of tumor-targeted MAbs by complexation with radiolabeled haptens have been developed. 

Radionuclides Used for RAIT

Tumoricidal effects produced by continuous low-dose irradiation from a tumor-targeted radiolabeled MAb. For therapy, α- and β-particle emitters are of practical relevance. There have been numerous investigations with a number of these radionuclides, but for use with whole antibodies, the most promising radionuclides are the β-emitters 131I, 90Y, and 177Lu. 90Y is a max-energy β-emitter (Emax: 2,280 keV; max range: 12 mm) with a 64-h half-life, while 131I has a higher half-life of 8.1 days with low-intermediate energy (610 keV, range: 2.0 mm). 131I is quickly removed from tumor cells after intracellular antibody catabolism so it is not suitable for use with internalizing MAbs. The forms of intracellularly trapped 131I have been designed by us and others for use with internalizing MAbs. A recent study of IMP-R4 template utilized for incorporating residualizing radioiodine for immuno-PET quantitation of de2-7 EGFR expression in glioma in a xenograft model using 124I-IMP-R4–labeled anti-EGFR antibody, ch806. Residualizing use of radioiodine method for clinical RAIT may be supplanted by the availability of the metallic radionuclide 177Lu, which has radiophysical properties similar to those of 131I and radiolabeling chemistry similar to that of 90Y.