A RANTES-ANTIBODY FUSION PROTEIN RETAINS ANTIGEN-SPECIFICITY AND CHEMOKINE FUNCTION

The successful eradication of cancer cells in the setting of minimal r esidual disease may require targeting of metastatic tumor deposits tha t evade the immune system. We combined the targeting flexibility and s pecificity of mAbs with the immune effector function of the chemokine RANTES to target established tumor deposits. We describe the construct ion of an Ab fusion molecule with variable domains directed against th e tumor-associated Ag HER2/neu, linked to sequences encoding the chemo kine RANTES (RANTES.her2.IgG3). RANTES is a potent chemoattractant of T cells, NK cells, monocytes, and dendritic cells, and expression of R ANTES has been shown to enhance immune responses against tumors in mur ine models. RANTES.her2.IgG3 fusion protein bound specifically to HER2 /neu Ag expressed on EL4 cells and on SKBR3 breast cancer cells as ass ayed by how cytometry, RANTES.her2.IgG3 could elicit actin polymerizat ion of THP-1 cells and transendothelial migration of primary T lymphoc ytes, RANTES.her2.IgG3 prebound to SKBR3 cells also facilitated migrat ion of T cells, RANTES.her2.IgG3 bound specifically to the CCR5 chemok ine receptor, as demonstrated by flow cytometry, and inhibited HIV-1 i nfection via the CCR5 coreceptor, RANTES.her2.IgG3, alone or in combin ation with other chemokine or cytokine fusion Abs, may be a suitable r eagent for recruitment and activation of an expanded repertoire of eff ector cells to tumor deposits.