Abstract
Tumor-specific monoclonal antibodies (mAbs) can efficiently target to tumors. The unique specificity of mAb makes it an excellent vector to deliver toxic or immunomodulatory molecules to the tumor microenvironment, leading to tumor destruction without severe side effects. In this study, three antitumor chemokines, Lymphotactin (Lptn), Macrophage inflammatory protein-1α (MIP-1α) and T cell activation gene 3 (TCA3) were fused with mAbs, resulting in two groups of immunochemokines: chS5A8-chemokines and L6-chemokines. Flow cytometry analysis showed that the two groups of immunochemokines can specifically bind to their respective tumor cells, 38C13 B cell lymphoma and CT-26/TAL6 colon carcinoma. Because of time limit, we focused the following studies on mAb-Lptn immunochemokines. In the chemotaxis assay, both chS5A8-Lptn and L6-Lptn showed the ability to induce T cells migration. The therapeutic effect of chS5A8-Lptn was evaluated on C3H/HeN mice. Surprisingly, we found that 38C13 cells did not form tumors in the syngeneic mice, C3H/HeN, a result different from what was reported in the literature and previous experience in our laboratory. After several trials, we concluded that this problem may come from the inconsistent quality of C3H/HeN mice from the animal supplier. The antitumor effect of L6-Lptn was evaluated on BALB/c mice against CT-26/TAL6 in a combination treatment with IL-12. The therapeutic effect of combination therapy was more effective than L6-Lptn or IL-12 monotherapy, but was not significantly different from a combination therapy with L6 plus IL-12. In another experiment, we also showed that combination therapy of L6-Lptn with L6-IL-2 or L6-IL-12 had no significant advantage over the L6-IL-2 or L6-IL-12 monotherapy. These results showed that L6-Lptn did not possess antitumor activity. It has been known that the concentration gradient of chemokine was important for guiding migration of specific lymphocytes. Since treatment with immunochemokines could only make an elevation of local chemokines but not a concentration gradient, and hence may fail to recruit the immune effector cells to the tumor site. This may explain why the immunochemokine strategy failed in cancer immunotherapy.