Abstract
Cobalamin uptake into cells is mediated by the CD320 receptor for transcobalamin-bound cobalamin. Optimum receptor expression is associated with proliferating cells and therefore, in many cancers this receptor expression is up regulated. Delivering drugs or toxins via this receptor provides increased targeting to cancer cells while minimizing toxicity to the normal tissues. Saporin conjugated monoclonal antibodies to the extracellular domain of TCblR were effectively internalized to deliver a toxic dose of Saporin to some cancer cell lines propagating in culture. Antibody concentration of 2.5 nM was effective in producing optimum inhibition of cell proliferation. The cytotoxic effect of mAb-Saporin appears to be dictated primarily by the level of receptor expression and therefore normal primary cells expressing low levels of CD320 were spared while tumor cell lines with higher CD320 expression were destroyed. Targeting the pathway for cellular uptake of vitamin B12 via the CD320 receptor with toxin-antibody conjugates appears to be a viable treatment strategy for certain cancers that over expresses this receptor.
Highlights
The transcobalamin receptor TCblR/CD320 [1] is ubiquitously expressed in most cell types and mediates uptake of transcobalamin (TC), a plasma protein saturated with cobalamin (Cbl, B12)
The present study extends this preliminary observation by demonstrating enhanced targeting and destruction of cancer cells by Saporin conjugated directly to monoclonal antibodies to the extracellular domain of TCblR/CD320
All three mAb-Saporin conjugates are fully functional in recognizing the target antigen with high affinity, an important requirement for mAbs to be used as carriers of drugs and toxins
Summary
The transcobalamin receptor TCblR/CD320 [1] is ubiquitously expressed in most cell types and mediates uptake of transcobalamin (TC), a plasma protein saturated with cobalamin (Cbl, B12). TCblR expression appears to be cell cycle associated with highest expression in actively proliferating cells and is substantially down regulated in quiescent cells [7,8,9] This differential expression of the receptor serves to provide optimum delivery of the vitamin to cells during the early phase of DNA synthesis. This process ensures adequate functioning of Cbl dependent enzymes, especially the methionine synthase that is essential for recycling of methyl folate to generate folates needed for purine and pyrimidine biosynthesis. The search for tumor specific markers and the strategies to utilize these in cancer therapy have been pursued for decades with mixed results. The present study extends this preliminary observation by demonstrating enhanced targeting and destruction of cancer cells by Saporin conjugated directly to monoclonal antibodies to the extracellular domain of TCblR/CD320
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