Antitumor potential of AvFc lectibody in non-small cell lung cancer

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PROJECT SUMMARY / ABSTRACT The goal of this project is to develop a novel tumor glycobiomarker-targeting agent against non-small cell lung cancer (NSCLC). NSCLC accounts for the majority of all lung tumors and is frequently diagnosed at an advanced stage with poor prognosis. Current therapies, including novel targeted drugs and immunotherapies, have led to improved outcomes but have had less efficacy in advanced disease, and several of these agents result in resistance. Given that a combination of multiple therapeutic strategies may be necessary to produce an optimal therapeutic outcome, development of novel therapeutic agents targeting a unique biomarker of NSCLC is warranted. Particularly, tumor-targeted immunotherapy that can boost an antitumor immune response might enhance the efficacy of immune checkpoint inhibitors. There is growing evidence for an aberrant increase of high-mannose glycans in the glycome of cancer cells, including those of NSCLC. To target this glycobiomarker, the applicant’s lab has developed Avaren-Fc (AvFc), a recombinant antibody-like molecule “lectibody” efficiently recognizing high-mannose glycans on the surface of malignant cells. The antitumor potential and safety of AvFc has been demonstrated in human A549 and H460 NSCLC xenograft challenge models using immunodeficient mice as well as in syngeneic B16F10 melanoma challenge models using immunocompetent C57bl/6 mice. In the latter model, AvFc treatment increased the infiltration of non-classical monocytes and other myeloid cells as well as CD4/CD8 T lymphocytes. Furthermore, immunohistochemical analysis revealed that AvFc can selectively recognize primary human NSCLC tumors over adjacent non-tumor lung tissues. Based on these findings, we hypothesize that AvFc may serve as a novel immunotherapeutic agent targeting tumor-associated high-mannose glycans in NSCLC. To substantiate the possibility in a more clinically relevant NSCLC model, the goal of this R21 project is to reveal the immunotherapeutic efficacy and tumor-targeting profile of AvFc in a conditional Kras/p53 mutation-driven NSCLC mouse model. In Specific Aim 1, we will determine and characterize the therapeutic effects of AvFc based on overall survival, immunohistochemistry of lung tumors, and immunophenotyping of lung-infiltrated immune cells. Additionally, we will assess the efficacy of AvFc in combination with the immune checkpoint blocker anti-PD-1 antibody. In Specific Aim 2, we will analyze biodistribution and tumor detection profiles of AvFc in the NSCLC mice, using a radiolabeled AvFc derivative in a microPET/CT imaging analysis. Building on our preliminary data, we will design and optimize radiolabeled AvFc derivatives to have an optimal pharmacokinetic profile and tumor-detection sensitivity. In particular, we will assess the capability of radiolabeled AvFc to detect tumor progression and metastasis. Collectively, the proposed research will provide critical information addressing the question of whether AvFc could be a viable immunotherapeutic and/or diagnostic agent against NSCLC. Should the answer be positive, the results will significantly facilitate further preclinical development of AvFc towards a Phase I clinical trial.