First‐in‐human study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of ALPN‐101, a dual CD28/ICOS antagonist, in healthy adult subjects

Yang, Jing; Lickliter, Jason D.; Hillson, Jan; Means, Gary; Sanderson, Russell J.; Carley, Kay; Tercero, Almudena; Manjarrez, Kristi L.; Wiley, Jennifer R.; Peng, Stanford L.

doi:10.1111/cts.12983

Cited by 13 publications

(19 citation statements)

References 42 publications

(89 reference statements)

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“…It stands to reason then that forced expression of T cell co-stimulatory molecules at the tumor site could help fully activate endogenous tumor-infiltrating T cells. We constructed HDAds encoding either inducible T cell costimulator ligand (ICOSL), OX40L, or 41BBL, for which agonistic antibodies have been tested in clinical trials [ 42 , 43 ], and confirmed cancer cell surface expression of these molecules after infection ( Figure 2 D). To evaluate the proof-of-principle that HDAd-derived co-stimulatory molecules enhance the function of tumor associated antigen-specific T cells (TAA-T cells), we tested the ability of HD 41BBL to enhance the cytotoxicity of TAA-T cells, as 41BB is expressed on CD8+ T cells after activation [ 44 ].…”

Section: Resultsmentioning

confidence: 99%

HydrAd: A Helper-Dependent Adenovirus Targeting Multiple Immune Pathways for Cancer Immunotherapy

Shaw

Porter

Biegert

et al. 2022

Cancers

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For decades, Adenoviruses (Ads) have been staple cancer gene therapy vectors. Ads are highly immunogenic, making them effective adjuvants. These viruses have well characterized genomes, allowing for substantial modifications including capsid chimerism and therapeutic transgene insertion. Multiple generations of Ad vectors have been generated with reduced or enhanced immunogenicity, depending on their intended purpose, and with increased transgene capacity. The latest-generation Ad vector is the Helper-dependent Ad (HDAd), in which all viral coding sequences are removed from the genome, leaving only the cis-acting ITRs and packaging sequences, providing up to 34 kb of transgene capacity. Although HDAds are replication incompetent, their innate immunogenicity remains intact. Therefore, the HDAd is an ideal cancer gene therapy vector as its infection results in anti-viral immune stimulation that can be enhanced or redirected towards the tumor via transgene expression. Co-infection of tumor cells with an oncolytic Ad and an HDAd results in tumor cell lysis and amplification of HDAd-encoded transgene expression. Here, we describe an HDAd-based cancer gene therapy expressing multiple classes of immunomodulatory molecules to simultaneously stimulate multiple axes of immune pathways: the HydrAd. Overall, the HydrAd platform represents a promising cancer immunotherapy agent against complex solid tumors.

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Section: Resultsmentioning

confidence: 99%

HydrAd: A Helper-Dependent Adenovirus Targeting Multiple Immune Pathways for Cancer Immunotherapy

Shaw

Porter

Biegert

et al. 2022

Cancers

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“…Subcutaneous KLH injection is the most frequently used administration route (21 out of 45 studies, Table 1 and Figure 2). (Curtis and Hersh, 1972;Brunner et al, 1973;Paty et al, 1975;Volkman et al, 1981;Ford and Burger, 1983;Bird et al, 1990;Ward et al, 1990;Snyder et al, 1993;Husby et al, 1994;Waldo et al, 1994;Fijter et al, 1996;Kantele et al, 1999;Rentenaar et al, 2002;Kraus et al, 2004;Miller et al, 2005;Kapp et al, 2010;Kantele et al, 2011;Hostmann et al, 2015;Belson et al, 2016;Giesecke et al, 2018;Yang et al, 2021) Other frequently used routes of administration include intramuscular and intradermal injections (Ashorn et al, 1986;Boelens et al, 2004;Birdsall and Rossen, 1983;Bird et al, 1990;Curtis and Hersh, 1972;Falconer et al, 1992;Ford and Burger, 1983;Kondratenko et al, 1997;Lange et al, 2003;Ochs et al, 1988;Otterhaug et al, 2021;Palestine et al, 1985;Powell et al, 1978;Salvaggio et al, 1969;Smith et al, 2004a;Smith et al, 2004b;Moldoveanu et al, 2004;Spazierer et al, 2009;…”

Section: Klh Immunization and Rechallengementioning

confidence: 99%

“…Analysis methods varied from enzyme-linked immunosorbent assay (ELISA) to hemagglutination assay (HA), radioimmunoassay (RIA), and cytometric bead array (CBA) (Table 2). The majority of the studies had used ELISA to quantify KLHspecific antibodies (Volkman et al, 1981;Palestine et al, 1985;Bird et al, 1990;Ward et al, 1990;Falconer et al, 1992;Husby et al, 1994;Waldo et al, 1994;Fijter et al, 1996;Kondratenko et al, 1997;Schuyler et al, 1997;Rentenaar et al, 2002;Lange et al, 2003;Smith et al, 2004a;Boelens et al, 2004;Smith et al, 2004b;Kraus et al, 2004;Moldoveanu et al, 2004;Miller et al, 2005;Spazierer et al, 2009;Kapp et al, 2010;Boulton et al, 2012;Milgrom et al, 2012;Hostmann et al, 2015;Poirier et al, 2016;Giesecke et al, 2018;Saghari et al, 2020;Otterhaug et al, 2021;Yang et al, 2021;Saghari et al, 2022).…”

Section: Assays For Quantification Of Systemic Humoral Responses Foll...mentioning

confidence: 99%

“…Based on the low IL-33 levels, a known Th2 response promoter, it seems unlikely that the Th2 response was induced by this cytokine. Moreover, the importance of increased IL-17 and IL-22 levels compared to placebo remain to be elucidated as Frontiers in Drug Discovery frontiersin.org Author article, year Intervention/Patient population Outcome Saghari M, et al, 2022(Saghari et al, 2022 Intervention: Amlitelimab in HVs ↓ humoral response, ↓ skin rechallenge response Yang J, et al, 2021(Yang et al, 2021 Intervention: Acazicolcept in HVs ↓ humoral response Otterhaug T, et al, 2021(Otterhaug et al, 2021 Intervention: Fimaporfin+light in HVs ↑ humoral response Swaminathan A, et al, 2019(Swaminathan et al, 2019 Intervention: Solar UVR in HVs = humoral response, ↓ skin rechallenge response, ↑ Th17/CD4 + T cell ratio Poirier N, et al, 2016(Poirier et al, 2016 Intervention: VEL-101 in HVs ↓ humoral response Hostmann A, et al, 2015(Hostmann et al, 2015 Intervention: Oral KLH feeding in HVs Primed/Immunized subjects: = humoral response, = skin rechallenge response, ↓ CD4 + T cell, IL-2, IL-17, CLA, IFN-γ, ↑ CD4 + T cell, IL-10 Kaufman M, et al, 2014 (Kaufman et al, 2014) Intervention: Natalizumab in RRMS = humoral response (compared to no treatment) Gallegos A, et al, 2013(Gallegos et al, 2013 Intervention: MBSR in HVs ↓ humoral response (compared to HVs) Ferbas J, et al, 2013(Ferbas et al, 2013 Patient population: SLE vs. HVs Predominance of IgG2 followed by IgG1 after 2nd immunization (compared to predominance of IgG1 in HVs), = B cell ELISpot response Boulton C, et al, 2012(Boulton et al, 2012 Intervention: Fingolimod in HVs ↓ humoral response (compared to no treatment) Kapp K, et al, 2010(Kapp et al, 2010 Intervention: Oral KLH feeding in HVs Non primed/immunized subjects: faster and ↑ humoral response, = skin rechallenge response, ↑ CD4 + T cells, ↓ CD4 + CLA + T cells, faster ↑ in CD4 + T cells (including IL-2, IL-4, IFN-γ, TNF, and integrin β7 producing cells) and proliferated CD4 + T cells after immunization Primed/Immunized subjects: ↓ CD4 + T cell IL-2, IFN-γ, and TNF and ↑ CD4 + T cell IL-4 and IL-10, ↓ CD4 + CLA + T cells Bingham C, et al, 2010…”

Section: Local Cellular and Molecular Klh Response Sizes And Variabilitymentioning

confidence: 99%

“…↑ humoral response (compared to no treatment) Ochs H, et al, 1988(Ochs et al, 1988 Patient population: HIV and PGL vs. HVs ↓ humoral response (compared to HVs) Palestine A, et al, 1985(Palestine et al, 1985 Intervention: Cyclosporine in uveitis = humoral response, ↓ skin rechallenge response, = lymphocyte proliferation (compared to no treatment) Berd D, et al, 1984(Berd et al, 1984 Patient population: Cyclophosphamide in cancer ↑ humoral response, ↑ skin rechallenge response (compared to no treatment) Paty J, et al, 1975(Paty et al, 1975 Patient population: SLE vs. HVs ↓ humoral response, ↓ lymphocyte proliferation (compared to HVs) Salvaggio C, et al, 1969(Salvaggio et al, 1969 Patient population: Atopics vs. HVs = humoral response, ↑ skin rechallenge response (compared to HVs) Frontiers in Drug Discovery frontiersin.org Gallegos et al, 2013;Kaufman et al, 2014;Hostmann et al, 2015;Poirier et al, 2016;Swaminathan et al, 2019;Otterhaug et al, 2021;Yang et al, 2021;Saghari et al, 2022). The remaining 17 studies evaluated the KLH responses in various patient populations (Salvaggio et al, 1969;Paty et al, 1975;Berd et al, 1984;Ochs et al, 1988;Sidell et al, 1990;Falconer et al, 1992;Wishahi et al, 1995;Fijter et al, 1996;Kondratenko et al, 1997;Valdez et al, 2000;Rentenaar et al, 2002;Lange et al, 2003;Boelens et al, 2004;Miller et al, 2005;Grant et al, 2008;Spazierer et al, 2009;…”

Section: Author Article Yearmentioning

confidence: 99%

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Characterization of KLH-driven immune responses in clinical studies: A systematic review

Saghari

Jansen

Grievink

et al. 2022

Front. Drug. Discov.

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The pharmacological activity assessment of novel immunomodulatory drugs in early-stage drug development is challenging as healthy volunteers do not express relevant immune biomarkers. Alternatively, the immune system can be challenged with keyhole limpet hemocyanin (KLH), a suitable antigen for studying adaptive immune responses. This report systemically reviews the KLH challenge in clinical studies focusing on the characterization of the KLH-driven systemic and local immune responses, identification of the KLH-induced biomarkers, and the evaluation of the effect of pharmacological interventions and diseases on the KLH response. A systematic literature review was carried out in PubMed spanning from 1967 to 2022. The systemic humoral KLH responses could be characterized by ELISA after 3 weeks following immunization. For the systemic cellular and molecular immune responses multiple KLH immunizations and the use of novel techniques such as flow cytometry and ELISpot yield optimal results. The objective evaluation of dermal KLH rechallenge allows for more accurate and sensitive quantification of the local response compared to subjective scoring. For the local cellular and molecular assays after KLH dermal rechallenge we also advocate the use of multiple KLH immunizations. Furthermore, oral KLH feeding, age, physical activity, alcohol consumption, stress, as well as certain auto-immune diseases also play a role in the KLH-induced immune response. Importantly, based on the KLH challenges, the effect of (novel) immunomodulatory drugs could be demonstrated in healthy volunteers, providing valuable information for the clinical development of these compounds. This review underlines the value of KLH challenges in clinical studies, but also the need for standardized and well-controlled methodology to induce and evaluate KLH responses.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022335419

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Non‐Redundant Roles of T Cell Costimulation Pathways in Inflammatory Arthritis Revealed by Dual Blockade of ICOS and CD28 with Acazicolcept (ALPN‐101)

Dillon

Evans

Lewis

et al. 2023

Arthritis & Rheumatology

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Objective. CD28 and inducible T cell costimulator (ICOS) appear to have nonredundant roles in T cell activation and adaptive immunity. We undertook this study to characterize in vitro and in vivo the therapeutic potential of acazicolcept (ALPN-101), an Fc fusion protein of a human variant ICOS ligand (ICOSL) domain designed to inhibit both CD28 and ICOS costimulation, in inflammatory arthritis.Methods. Acazicolcept was compared in vitro with inhibitors of either the CD28 or ICOS pathways (abatacept and belatacept , prezalumab [anti-ICOSL monoclonal antibody]) in receptor binding and signaling assays, and in a collagen-induced arthritis (CIA) model. Acazicolcept was also compared in cytokine and gene expression assays of peripheral blood mononuclear cells (PBMCs) from healthy donors or rheumatoid arthritis (RA) or psoriatic arthritis (PsA) patients stimulated with artificial antigen-presenting cells (APCs) expressing CD28 and ICOS ligands*.Results. Acazicolcept bound CD28 and ICOS, prevented ligand binding, and inhibited human T cell functional interactions, matching or exceeding the activity of CD28 or ICOS costimulatory single-pathway inhibitors tested individually or in combination. Acazicolcept administration significantly reduced disease in the CIA model and more potently than abatacept. Acazicolcept also inhibited proinflammatory cytokine production from stimulated PBMCs in cocultures with artificial APCs and demonstrated unique effects on gene expression distinct from those induced by abatacept, prezalumab, or a combination of both.Conclusion. Both CD28 and ICOS signaling play critical roles in inflammatory arthritis. Therapeutic agents such as acazicolcept that coinhibit both ICOS and CD28 signaling may mitigate inflammation and/or disease progression in RA and PsA more effectively than inhibitors of either pathway alone.*[Correction added on 31 May 2023, after first online publication: In the Abstract, at the end of the Methods, the text was changed from "CD28 and ICOSL" to "CD28 and ICOS ligands".] Supported by Alpine Immune Sciences, Inc.

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First‐in‐human study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of ALPN‐101, a dual CD28/ICOS antagonist, in healthy adult subjects

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 13 publications

References 42 publications

HydrAd: A Helper-Dependent Adenovirus Targeting Multiple Immune Pathways for Cancer Immunotherapy

HydrAd: A Helper-Dependent Adenovirus Targeting Multiple Immune Pathways for Cancer Immunotherapy

Characterization of KLH-driven immune responses in clinical studies: A systematic review

Non‐Redundant Roles of T Cell Costimulation Pathways in Inflammatory Arthritis Revealed by Dual Blockade of ICOS and CD28 with Acazicolcept (ALPN‐101)

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