ID: 75: Unraveling the properties required for an effective therapeutic antibody targeting a chemokine

The control of cell migration by chemokines is mediated by interactions with seven transmembrane G protein-coupled receptors and cell surface proteoglycans. Monoclonal antibodies (mAbs) are a successful class of drugs especially when targeting cytokines. However, there has been limited success when targeting a chemokine. In order to further define what is required to achieve therapeutic efficacy when targeting a chemokine with a mAb, we have dissected the characteristics of two anti-murine CXCL10 mAbs. Interestingly, despite having similar affinities and selectivity for CXCL10, they exhibit different key properties. Both mAbs are able to inhibit receptor mediated events such as chemotaxis in vitro, albeit with different potencies yet only one shows efficacy in several animal models of human disease. In addition, the PK of the two mAbs in mice was significantly different: the active mAb had a PK profile characteristic of IgGs with a T1/2 of 18 days whereas the other was rapidly cleared. In contrast to the belief that the active form of chemokine is that bound to cell surface GAGs, the mAb that showed activity in vivo did not recognize cell bound chemokine, whilst the mAb that was rapidly cleared did, leading to a proposal of a new paradigm in chemokine biology. Furthermore, in view of the unexpected abundance of chemokine protein, we have identified a pH dependent antibody which is could inhibit multiple target antigens, through release of the target in the endosomal compartment. Their head to head comparison in a CXCL10 dependent disease model will be presented.