CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

412

10e8 4/iMAb Bispecific Antibody for Immunoprophylaxis Against High-Dose Intravenous SHIV Exposure Matthew S Parsons 1 , Hannah A. King 2 , Decha Silsorn 1 , Jumpol Sopanaporn 1 , Panupat Nadee 1 , Dutsadee Inthawong 1 , Rawiwan Imerbsin 1 , Caroline Subra 2 , Lindsay Wieczorek 2 , Victoria Polonis 2 , Yaoxing Huang 3 , David D. Ho 3 , Sandhya Vasan 2 , Julie Ake 2 , Diane L. Bolton 2 1 Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand, 2 US Military HIV Research Program, Silver Spring, MD, USA, 3 Aaron Diamond AIDS Research Center, New York, NY, USA Background: A lead strategy for preventing HIV transmission is the passive provision of broadly neutralizing antibodies (bNAbs). Various investigators have validated this approach in nonhuman primate (NHP) models of HIV exposure. Experiments in NHPs have primarily focused on preventing viral transmission across anogenital mucosae. In humans, the antibody-mediated prevention (AMP) trial demonstrated that passively administered VRC01 bNAb prevents the transmission of neutralization-sensitive but not resistant HIV strains, emphasizing the urgent need for bNAbs with greater breadth and potency for immunoprophylaxis strategies. Methods: We developed a nonhuman primate model of immunoprophylaxis in the context of high-dose intravenous HIV exposure. We assessed the 10e8.4/ iMAb bispecific antibody, which targets the membrane- proximal external region of the HIV envelope and the CD4 receptor, as an immunoprophylaxis agent. We measured the in vitro neutralization activity of 10e8.4/iMAb using the TZM-bl cell line-based neutralization assay. We intravenously infused three animals with 30mg/kg of 10e8.4/iMAb and three control animals with PBS. One hour later, we challenged all animals intravenously with a high dose (~50,000 TCID 50 ) of SHIV- BG505. We performed antibody-mediated CD8+ lymphocyte depletions eight weeks after the viral challenge in aviremic animals to assess for subclinical/occult infections. Results: The SHIV-BG505 challenge virus was sensitive to 10e8.4/iMAb (IC 50 <0.01 ug/ml). Control animals developed plasma viremia one week after high-dose intravenous viral challenge (peak: 8.7E6 – 1.1E7 copies/ml). Animals passively administered 10e8.4/iMAb exhibited no evidence of viral infection, even five weeks after systemic depletion of CD8+ lymphocytes. Conclusion: Passive intravenous provision of potent anti-HIV bispecific bN Abs is a highly promising immunoprophylaxis strategy for high-dose intravenous HIV exposure. Long Half-Life Broadly Neutralizing Killer Bispecifics Against HIV-1: Harnessing the Immune System Sukanya Ghosh , Maya Singh, Mansi Purwar, Daniel Kulp, Luis J. Montaner, David B. Weiner Wistar Institute, Philadelphia, PA, USA Background: HIV-1 remains significant global health challenge, requiring continuous efforts to develop innovative therapeutic approaches. Clinical use of mAb needs multiple infusions and for BiTEs is limited by short half-life in blood, demanding continuous infusion resulting in high costs inconvenience and time- consumption. We describe the development of DNA-launched, bispecific T cell engagers that redirect T cells towards killing target HIV infected cells. These are highly specific Broadly neutralizing Killers (BnKs) that demonstrate long half-lives (LHL) in-vivo. Methods: We designed DNA-launched LHL- BnKs with bispecific scFvs and a Fc fragment having Fc effector- null mutations to abrogate Fcγ receptor binding. We evaluated in-vitro and in-vivo expression of DNA launched LHL-BnKs and characterized functionality. ELISA and flow cytometry were used to demonstrate binding studies, pseudo-neutralization assays to test neutralizing potential against a global virus panel. A novel cell based Xcelligence assay was designed which uses impedance as a readout for killing activity. In-vivo pharmacokinetics were evaluated by inoculating the DNA launched LHL-BnKs in BALB/c mice. Results: DNA launched PGDM1400, 3BNC117 and PGT121 LHL-BnKs respectively were designed and optimized for expression both in-vitro and in-vivo. Binding studies demonstrate that these molecules bind to CD3 in a concentration dependent manner. They also demonstrated binding to CD3+T cells and neutralized a global panel of HIV-1 Tier 2/3 viruses with high potency and specificity. The LHL-BnKs displayed potent killing of HIV-1 infected target cells with nanogram/ml IC 50 for killing. Combination therapy of 10-1074 and 3BNC117 did significantly reduce viral rebound in clinical trials where the groups received up to 8 infusions of 3BNC117 during the 24-week period. Our data suggests that after single inoculation of 50ug DNA, plasma concentration of ~10ug/ml was

411

ABBV-382, an Anti-α4β7 Ab That Enhances HIV-1 Antigen Presentation for Immune- Mediated Viral Control Teresa Ng , Gautam K. Sahu, Domenick E. Kennedy, Tatyana Dekhtyar, Renee Miller, Liangjun Lu, Dolonchampa Maji, Silvino Sousa, Keenan Taylor, Sahana Bose, Joel F. Cohen-Solal, Axel Hernandez Jr., Victoria A. Pitney, Melanie J. Patterson, Jochen Salfeld Abbvie, Inc, Chicago, IL, USA Background: The α4β7 integrin plays an important role in the pathogenesis of HIV-1 infection. It is a heterodimeric receptor expressed on different immune cells. Expression of α4β7 on peripheral CD4+ T cells predicts HIV-1 acquisition and disease progression. Recent study showed that α4β7 is present on the envelope of HIV-1 virions, which suggests that α4β7 could be a highly conserved target for HIV-1 treatment. Methods: ABBV-382, a humanized mouse anti-human α4β7 mAb, has been evaluated in different biochemical, virological, immunosafety, and immunopeptidomics studies to characterize its properties and determine its mechanisms of action for HIV-1 intervention. Results: ABBV-382 demonstrated high binding affinity to α4β7 and blocked the interaction of α4β7 with its ligand MAdCAM-1. The binding profile of ABBV-382 to human FcγRs was similar to that of a typical human IgG1 mAb, but it did not induce ADCC or ADCP activity in vitro. ABBV-382 blocked the MAdCAM-1- mediated co-stimulation of CD4+ T cells, and HIV-1 replication in these treated cells. It also inhibited the interaction of α4β7 with HIV-1 gp120, and is therefore proposed to inhibit the cell-to-cell viral spread mediated by this interaction. Consistent with the report that α4β7 is present on the surface of HIV-1 virions, ABBV-382 could bind to virions from different HIV-1 strains to form immune complexes (ICs). These ICs could engage different FcγRs through the Fc domain of ABBV-382 in vitro. When the ICs were incubated with antigen presenting cells (APCs), they were phagocytosed in a Fc-dependent manner. Immunopeptidomics analyses demonstrated that the internalized ICs were processed, and HIV-1 peptides were presented by MHC class II on APCs, a mechanism that is proposed to enhance HIV-1 antigen presentation to T cells. Conclusion: Our study results provide evidence of the antiviral and immunomodulatory properties of ABBV-382 through two main mechanisms: (1) Direct antagonism of the interaction of α4β7 with its ligand MAdCAM-1 or HIV-1 gp120, leading to inhibition of HIV-1 replication or cell-to cell viral spread, respectively, and (2) Enhanced viral antigen presentation to T cells enabled by the Fc-dependent uptake of ICs (HIV-1 virions and ABBV-382) by APCs. Taken together, ABBV-382 demonstrates favorable biological characteristics and novel mechanistic properties supporting its clinical evaluation as an immune-based intervention for HIV-1 viral control. Disclosure: The design, study conduct, & financial support were provided by AbbVie.

Poster Abstracts

413

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