Development of a universal prodrug approach for antibody based therapeutics

Project Summary Therapeutic antibodies against tumor targets have become standard therapeutic approach in oncology and have significantly improved clinical outcomes in liquid and solid tumorsIn additiontherapeutic antibodies against immune checkpoint receptors have shown a great therapeutic potential in oncology when administered alone and in combinationHoweveradverse events related to presence of specific targets in normal tissuesespecially in therapies combining two or more therapeutic antibodiescan limit dosing and thus efficacy of therapiesas well as prevent potential targets from being tested in clinical trialsThusa technology restricting therapeutic action to tumor sites would have a major impact on clinical efficacy of antibody therapeuticsScalmiBio proposes to develop universal platform for converting any therapeutic antibody into activatable prodrugOur technology acts to minimize interaction of an antibody therapeutic with normal tissueand maximizes its target binding capability within tumorWe achieve this by exploiting tumorandapos s own deregulated featureactivated proteasesOur technology thus allows antibody therapeutics to be activated in tumors by specific tumor present proteasesThe goals of this project aredevelop a novel technology that turns any therapeutic antibody into prodrug activated by tumor specific proteases andconvert an existing anti CTLAtherapeutic antibody into anti CTLAantibody prodrugIn thisyear feasibility study we will focus onFirstoptimizing our universal shield which blocks interaction with target in normal tissues to generate anti CTLAantibody prodruga validated target of great therapeutic potential in immuno oncologySeconddesignoptimizeand experimentally validate protease substrates for tumor specific therapeutic antibody activationProtease substrates will be optimized for maximal cleavage in tumor tissues and minimal cleavage in serumusing mass spectrometry assayOur collaboratorOmix Technologies has innovated chromatographic separations and mass spectrometry based data acquisition to develop high throughput proteomics platformTheir methodology enables analysis of highly powered sample sets in a timeand cost efficient mannerThirdour technology and protease substrates will be validated in vivo in mouse colon carcinoma syngeneic mouse model sensitive to anti CTLAimmunotherapyScalmiBioandapos s technology platform will provide several benefits over typical antibody therapeuticminimize unwanted side effects of antibody therapeuticsunlock potential of new targetsresult in more predictable pharmacokinetics Project Narrative Therapeutic antibodies are moving to first line therapy in oncology and are significantly improving clinical outcomeshoweverhigh grade adverse side effects can limit treatment optionsA technology restricting therapeutic action to tumor site would enable use of novel combination treatmentsuse of higher therapeutic dosesand limit side effectsIn this project we propose development of a novel technology that will convert any therapeutic antibody into a prodrug activated specifically within tumorand apply it to generate anti CTLAantibody prodrug!