Clinical Translation of an Anti-Metastatic Antibody for Breast Cancer Therapy

DESCRIPTION provided by applicant Translational studies are proposed to support the continued development of the JAA F antibody based therapy to address the critical need for a safe and effective treatment for metastatic breast cancer including triple negative breast cancers Building on the success of our Phase I project the overarching objectives of the Phase II application are to advance translational studies with humanized JAA F hJAA F These novel IgG antibodies binds with high specificity to the pancarcinoma Thomsen Friedenreich glycoantigen TF Ag Gal GalNAc alpha which is a unique target expressed on the surface of about of breast colon bladder prostate and other carcinomas but not on normal tissues The successful generation of humanized and one chimeric JAA F constructs which have the same unique chemical specificity for TF Ag as our patented mouse monoclonal antibody mJAA F directly supports the hypothesis of our Phase I application that humanization of JAA F can yield an antibody of the same chemical and biologic specificity as the original mJAA F In addition there is active progress on generation of up to an additional humanized constructs that will be evaluated to identify lead antibody candidates The hypothesis of the Phase II application is that humanized constructs hJAA F can be used therapeutically to create a survival advantage for patients with breast cancers including triple negative breast cancers through direct killing and by blocking tumor cell spread Specific aims of this application are focused on identifying lead drug candidates and generating preclinical data in support of an Investigational New Drug IND application for therapeutic and diagnostic applications of hJAA F in breast cancer patients Aim will identify lead antibody candidates hJAA F constructs one of which supports the use of the antibody as a direct cancer immunotherapeutic agent and the second which supports the use as an antibody drug conjugate Both candidates will demonstrate high chemical and biological specificity for TF Ag positive tumors The lead immunotherapeutic candidate will have high antibody directed cellular cytotoxicity ADCC activity and the lead candidate for an antibody drug conjugate will have rapid tumor cell internalization Aim will assess the efficacy of hJAA F constructs on tumor growth rate in a xenograft human breast cancer model in Nude mice Efficacy studies will be conducted with the construct having optimal ADCC activity and the construct with optimal internalization will be tested as an antibody linker maytansine derivative Aim will conduct pharmacokinetic studies of these hJAA F constructs in mice with and without tumors Evaluation of the pharmacokinetics of hJAA F constructs is critically important to thePUBLIC HEALTH RELEVANCE The Phase I STTR project successfully produced humanized versions of our patented mouse monoclonal antibody mJAA F which has anti metastatic properties and reacts with of the human breast tumor lines tested It is hypothesized that the humanized hJAA F can be used therapeutically to create a survival advantage for patients with breast cancers including triple negative breast cancers through direct killing and by blocking tumor cell spread Preclinical data will be generated in support of an Investigational New Drug IND application for therapeutic and diagnostic applications of hJAA F in breast cancer patients