Development of Multispecific Antibodies for the treatment of Methicillin Resistant Staphylococcus ‎aureus MRSA infection

Abstract Through this project we propose to develop a therapeutic antibody against Staphylococcus aureus S a that simultaneously targets multiple secreted S a toxins as well as a cell surface target in a molecule that also contains a functional human IgG Fc domain S aureus infections are very common and their treatment is becoming more complex due to broadening antibiotic resistance Inhibrx has developed a platform where multiple camelid heavy chain only variable domains VHHs are joined end to end together with an Fc effector domain in any order to produce multi valent multi specific molecules targeting multiple epitopes on a single target or multiple targets We have already developed a tetravalent bispecific heavy chain only antibody with specificity against five S a toxins We propose to combine this antibody with a bacterial surface binding component to create a multi specific anti MRSA antibody We hypothesize that toxin blocking functionality will protect immune cells recruited to the site of infection while cell binding capability will enable opsonization of S a followed by its clearance We have targeted two highly conserved S a cell surface proteins for development of antibodies Protein A and EFB and identified a number of candidate high affinity antibodies against either of these targets Importantly as Protein A binds the Fc region of antibodies in a non immune fashion preventing efficient opsonization of the bacterium Inhibrx has integrated a proprietary Fc domain that does not bind Protein A into our anti Protein A targeting antibodies producing antibodies that avoid non immune Protein A binding In the present application we propose to select bacterial binding antibodies from among the above candidates and use them to create hexavalent multi specific antibodies that incorporate toxin blocking VHHs targeting five S a toxins together with cell surface binding VHHs and a Protein A resistant Fc domain all in one antibody therapeutic As the component antibodies from which the VHHs for our candidate therapeutic are taken are camelid in origin we propose in Specific Aim to utilize Inhibrx s humanization strategy to make the antibody compatible with human administration In Specific Aim our lead cell targeting antibodies will be compared for binding in the presence of their natural substrates and to whole bacteria in order to select lead antibodies for one or both targets for development of multi specific antibody Finally in Specific Aim the humanized lead toxin blocking antibodies and the humanized EFB and Protein A binding antibodies selected in Specific Aim will be combined in various formats using the Inhibrx platform A lead therapeutic antibody will be chosen based on toxin blocking and bacterial binding capabilities Multi specific antibodies will then be tested in in vitro functional studies as well as in vivo murine models of S a infection At the conclusion of Phase I we will be ready to apply for Phase II funding to perform PK and IND enabling studies in NHPs after which point Inhibrx will have demonstrated pre clinical efficacy of an unparalleled anti MRSA therapeutic Narrative Staphylococcus aureus S a infections including Methicillin resistant S a MRSA are very common and their treatment is becoming more complex due to broadening antibiotic resistance Inhibrx has developed a platform to create antibodies composed of multiple modules that can simultaneously target bacteria on multiple fronts We propose to use this platform to produce an unparalleled therapeutic that targets both S a itself and the mechanism of action by which it exerts its toxicity There are no approved antibody therapeutics for the treatment of S a and therefore Inhibrx s proposed antibody will likely establish best in class status