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Poster #LB-082 In Vivo Efficacy and Pharmacodynamic ... Poster #LB-082 In Vivo Efficacy and Pharmacodynamic Analysis of RTX-321, an Engineered Allogeneic Artificial Antigen Presenting

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  • Poster #LB-082 In Vivo Efficacy and Pharmacodynamic Analysis of RTX-321, an Engineered Allogeneic Artificial Antigen Presenting Red Cell Therapeutic

    Mellissa J. Nixon*, Xuqing Zhang*, Shamael Dastagir, Albert Lee, Mengyao Luo, Annie Khamhoung, Andrea Schmidt, Douglas C. McLaughlin, Viral Amin, Chris Moore, Jennifer Mellen, Laurence Turka, Thomas J. Wickham, and Tiffany F. Chen

    The American Association for Cancer Research Annual Meeting/June 22-24, 2020

    INTRODUCTION

    The risk of cancer is strongly associated with human papillomavirus (HPV) infection, with the high-risk strain, HPV 16, accounting for approximately 70% of all cervical cancers and 80% of head and neck cancers associated with HPV infection.1,2 HPV 16-positive (HPV 16+) malignancies remain a critical area of unmet need for new and innovative treatment options.

    Red Cell Therapeutics™ (RCTs) are a new class of allogeneic, off-the-shelf cellular therapeutic candidates for the treatment of cancer and autoimmune diseases. RCTs are engineered to mimic human immunobiology and induce a tumor-specific immune response by expanding tumor-specific T cells against a target antigen in vivo. Rubius Therapeutics’ first artificial antigen-presenting cell (aAPC) product candidate, RTX-321, is for the treatment of HPV 16+ cancers.

    OBJECTIVES

    • To demonstrate the direct interactions of a Rubius aAPC and antigen-specific cells in vitro

    • To demonstrate that this interaction occurs in vivo and induces long-lasting anti-tumor immunological memory

    • To demonstrate that aAPCs can promote anti-tumor immune responses and correlate pharmacodynamic changes with anti-tumor response

    • To demonstrate RTX-321 expansion and activation of antigen-specific human T cells in vitro

    Figure 1: The RED PLATFORM® Is Designed to Generate Allogeneic, Off-the-Shelf Cellular Therapies, Including RTX-321

    MHC = major histocompatibility complex.

    • The enucleated reticulocytes are RCTs that express hundreds of thousands of biotherapeutic proteins on the cell surface

    • Universal, scalable, and consistent manufacturing process

    Figure 2: RTX-321 Is a Cellular Therapy That Expresses Signals 1+2+3 for T Cell Activation

    RTX-321 consists of CD34+ stem cell–derived, allogeneic, engineered, human-enucleated red cells expressing human

    leukocyte antigen (HLA)-A*02:01 and ββ2 microglobulin with HPV 16 oncoprotein E7 peptide (HLA-A2-HPV; Signal 1), 4-1BB

    ligand (4-1BBL; tumor necrosis factor superfamily member 9; Signal 2), and a fusion protein of interleukin-12 (IL-12; Signal 3)

    p40 and p35 subunits on the cell surface.

    MHC = major histocompatibility complex; RTX-321 = RTX-HPV-4-1BBL-IL-12 product candidate; TCR = T cell receptor.

    RUBIUS THERAPEUTICS TERMINOLOGY

    • RCT = experimental construct

    • RTX = Red Cell Therapeutic™ product candidate

    • mRBC = mouse surrogate experimental construct

    TCR Signal 1 Tumor Antigen: HPV16 E7

    RTX-321 RTX-321

    MHC I (HLA-A2)

    T Cell

    Signal 3 Cytokine:

    IL-12

    Signal 2 Co-Stimulatory Agonist: 4-1BBL

    Figure 5: mRBC-321 Treatment Significantly Expands Antigen-Specific T cells in both the Blood and Tumor, which Correlates with Polyfunctionality within the Tumor

    (A) CD45.1 Pep Boy mice were inoculated subcutaneously with 2×106 EG7.OVA cells. When the tumors reached a volume of approximately 175 mm3, the animals

    were randomized and treated with 1×106 naïve OT1 cells. After, 1×109 mRBC-CTRL or a dose titration of mRBC-321 (1×109, 2.5×108) was administered on Days 0 and 3.

    TCRβ immunosequencing analysis was performed to determine OT1 frequency in blood on Day 0 (pre–mRBC-321 dose), 7 (post–mRBC-321 dose) and in the tumor

    on Day 7. (B) OT1 productive frequency significantly increased in the post-treatment blood and within the tumor of mRBC-321–treated mice. (C) As measured by

    flow cytometry, polyfunctionality (%Granzyme B+ IFNγβ+ ) in the tumor-infiltrating OT1 cells was significantly increased in mRBC-321–treated mice. Data points

    represent the mean ± standard deviation of 5 mice; one-way ANOVA compared to mRBC-CTRL within timepoints; *P