Final Report Summary - TROJA (Targeting Receptors Of Jointly Assembled Ligand-Drug Constructs)
The TROJA project was an investigative bioengineering study of the exploitation of specific endocytic receptors for targeting small molecule drugs to specific cells in order to improve medical therapy. The major line of the proposal concerned the construction of combinatory drugs for targeting the haptoglobin-hemoglobin receptor CD163 expressed in the monocyte-macrophage system. The platform applies to a broad spectrum of diseases such as inflammatory diseases, various infections and certain cancers which all have CD163-expressing macrophages or malignant derivatives as key cell type in the pathogenesis of the disease.
A number of different ligand and antibody drugs conjugates for binding to CD163 were designed and produced. For studies of conjugates with an anti-inflammatory effect, the project focused on anti-CD63 antibodies conjugated to potent synthetic glucocorticoid steroids, which are well-known to have strong anti-inflammatory efficacy. Testing of in vivo rodent and pig models showed a convincing effect of conjugated synthetic glycocorticoid targeted to macrophage CD163. The conjugates have approximately 50-fold higher efficacy than free glycocorticoid. At the same time the systemic effect of the steroid in non-macrophages is so far not measurable thus suggesting that the serious side effects often seen with glucocorticoid therapy can be avoided if this kind of conjugate therapy is used. For studies of conjugates with a cytotoxic effect applicable for cancer treatment, the studies focused on a special type of liposomes particles where antibodies were linked to the liposomes for targeting to the CD163 expressing cells. In vitro studies in vivo testing in mice revealed a clear and strong cytotoxic effect, and the research is now continued in different cancer models. Strong attempts are now in progress to bring this type of anti-inflammatory and cytotoxic conjugates into human clinical trials.
A number of different ligand and antibody drugs conjugates for binding to CD163 were designed and produced. For studies of conjugates with an anti-inflammatory effect, the project focused on anti-CD63 antibodies conjugated to potent synthetic glucocorticoid steroids, which are well-known to have strong anti-inflammatory efficacy. Testing of in vivo rodent and pig models showed a convincing effect of conjugated synthetic glycocorticoid targeted to macrophage CD163. The conjugates have approximately 50-fold higher efficacy than free glycocorticoid. At the same time the systemic effect of the steroid in non-macrophages is so far not measurable thus suggesting that the serious side effects often seen with glucocorticoid therapy can be avoided if this kind of conjugate therapy is used. For studies of conjugates with a cytotoxic effect applicable for cancer treatment, the studies focused on a special type of liposomes particles where antibodies were linked to the liposomes for targeting to the CD163 expressing cells. In vitro studies in vivo testing in mice revealed a clear and strong cytotoxic effect, and the research is now continued in different cancer models. Strong attempts are now in progress to bring this type of anti-inflammatory and cytotoxic conjugates into human clinical trials.