Targeting TGF-beta activation in tumors

Targeting TGF b activation in tumors Abstract Transforming growth factorTGFdrives immune dysfunction in the tumor microenvironment by inducing regulatory T cellsTregsand inhibiting cytolytic CDT cells and helper ThcellsTGF b is ubiquitously expressed in mammals as isoforms TGF bbandbbut is maintained in an inactive form by non covalent interaction with its propeptidethe latency associated domain of TGF bLAPThe integrin avbbinds to the LAP of TGF band TGF band mediates their activationGermline or conditional genetic deletion studies have revealed that integrin avbmediated activation of TGF b is essential for the in vivo activation of TGF band thus avbacts as a key modulator of TGF b functionIn generalintegrins are adhesion molecules and mediate the attachment of cells to extracellular matrix proteinsIntegrin avbrecognizes an Arg Gly AspRGDmotif and interacts with fibronectinvitronectinand latent TGFisoformsalthough it binds considerably more strongly to latent TGFthan to other RGD containing proteinsOzawaDespite the clear association of TGF b signaling and T cell functionfew therapies that target TGF b have been successfullargely due to pan inhibitor toxicityTo address this therapeutic challengewe have identified a mouse monoclonal antibodyAMHAthat selectively blocks the interaction of the human integrin avbwith its ligandlatent transforming growth factor bTGF bThe AMHAantibody is unique in that it selectively perturbs the avbmediated activation of TGF b isoformsandand does not inhibit TGF bwhich lacks an integrin binding RGD motifAdditionallybecause of redundant activities of other av integrinscell adhesion is not perturbed by AMHAThis affords a higher degree of selectivity in perturbing only integrin avbmediated activation of TGF b activation and not the residual cell adhesion propertieswhich may be undesirable to inhibitIn additionglobal inactivation of TGF b is likely to have undesirable side effects since TGF b is an essential homeostatic epithelial and immune effectorIn Phasewe will identify high affinity humAbs that inhibit avbmediated activation of TGF bthen rank order them in vitro for their ability to inhibit TGF b activation and to modulate T cell activityWe will also evaluate them in a small animal model as monotherapy and in combination with anti PDWe are confident that a novel therapy will result from this more selective approach NarrativeMany cancer patients fail to respond to immunotherapeutics because of down regulation of cytolytic T cell responses and exclusion from tumorsWe have identified a new therapeutic that inhibits immunosuppression by regulatory T cells and increases intratumoral T cell infiltrationThis novel cancer drug will enhance the body s immune responses against tumor cells and increase the effectiveness of other immunotherapies