Pretargeted Radioimmunotherapy for B-Cell Lymphomas

Abstract

Relapsed or treatment refractory B-cell lymphomas are currently incurable with conventional chemotherapy and radiation treatments. High-dose chemoradiotherapy and stem cell transplantation can cure some patients with relapsed or refractory lymphoma, but the majority of such patients die of progressive disease. We have investigated the potential utility of pretargeted radioimmunotherapy using monoclonal antibody-streptavidin, immunoconjugates, and fusion proteins in combination with N-acetylgalactosamine dendrimeric clearing agent and radiometallabeled 1,4,7,10-tetraazacyclododecane-N,N ¶,N 00 ,NØ-tetraacetic acid biotin for treatment of lymphomas using mouse and primate models.We have targeted a variety of cell surface antigens, including CD20, CD22, CD45, and HLA-DR, using conventional and pretargeted radioimmunotherapy. These studies showed the marked superiority of pretargeted radioimmunotherapy for each of the antigenic targets in terms of superior biodistributions, more complete tumor regressions, and longer survival. We are optimistic that this novel approach will provide a meaningful prolongation of survival for patients with relapsed or refractory lymphomas.

Self-assembly of carbon nanotubes and antibodies on tumours for targeted amplified delivery

“…This pre-targeting agent is followed by a rapidly cleared second-step agent, armed with cytotoxic or diagnostic effectors, that has a high-affinity for the initial agent. This interaction may involve streptavidin-biotin 18 , bispecific antibody-hapten 19 , oligonucleotide hybridization 20 , or covalent ‘click’ chemistry 21 interactions. This approach allows for improved ratios of the cytotoxic or imaging agent in the tumour to that in the blood.…”

A Novel Bispecific, Trivalent Antibody Construct for Targeting Pancreatic Carcinoma

“…Preclinical studies in xenograft models of colorectal cancer and lymphoma have suggested that delivery of radionuclides with pretargeting procedures can provide a significant therapeutic advantage over directly radiolabeled antibodies (11)(12)(13)(14)(15)(16). In addition, we have shown that pretargeting procedures can be used in combination with 99m Tc or 124 I for superior imaging capability over directly radiolabeled antibody fragments (17,18).…”

“…A SacII/AgeI restriction fragment containing the coding sequence for the heavy chain constant domains (C H 1-C H 3), which was excised from a pdHL2 vector for hPam4 IgG expression, was replaced with a SacII/AgeI fragment that was excised from the plasmid vector CH1-DDD2-Fab-hMN-14-pdHL2, and contains the coding sequence for C H 1 fused to a DDD2 peptide via a flexible linker. 111 In, have been reported (15). The hapten-peptide is divalent with respect to reactivity with mAb-679 (anti-HSG).…”

Targeted Cell Uptake of a Noninternalizing Antibody Through Conjugation to Iron Oxide Nanoparticles in Primary Central Nervous System Lymphoma

“…They are used in combination with biotinylated radioisotopes in radioimmunotherapy to target cancer cells while limiting radiation exposure to healthy tissue. This targeting strategy has been particularly successful in treating systemic lymphomas (20,43).…”