Human Immunoglobulin G1 Monoclonal Antibody Research Articles

Teprotumumab: The Dawn of Therapies in Moderate-to-Severe Thyroid-Associated Ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is a potentially sight-threatening ocular disease. About 3-5% of patients with TAO have severe disease with intense pain, inflammation, and sight-threatening corneal ulceration or compressive optic neuropathy. The current treatments of TAO are often suboptimal, mainly because the existing therapies do not target the pathogenesis of the disease. TAO mechanism is unclear. Ocular fibrocytes express relatively high levels of the functional TSH receptor (TSHR), and many indirect evidences support its participation. Over expression of insulin-like growth factor-1 receptor (IGF-IR) in fibroblasts, leading to inappropriate expression of inflammatory factors, production of hyaluronic acid and cell activation in orbital fibroblasts are also possible mechanisms. IGF-1R and TSHR form a physical and functional signaling complex. Inhibition of IGF-IR activity leads to the attenuation of signaling initiated at either receptor. Teprotumumab (TMB) is a human immunoglobulin G1 monoclonal antibody, binding to IGF-IR. Recently two TMB clinical trials had been implemented in TAO patients, indicating dramatic reductions in disease activity and severity, which approved its use for the treatment of TAO in the US. This review summarizes the treatments of TAO, focusing on the pathogenesis of IGF-1R in TAO and its application prospects.

P80.01 A Multicenter, Randomized, Phase 3 Trial of Penpulimab in Combination With Anlotinib or Chemotherapy as First-Line Treatment in Advanced NSCLC

Penpulimab, a human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) directed against human programmed cell death-1 (PD-1), was engineered to optimize receptor occupancy by improving duration of drug binding, and to eliminate Fc-mediated effector function that compromises anti-tumor immune cell function. Anlotinib, an antiangiogenic multi-target tyrosine kinase inhibitor. Chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC). A combination of the PD-1 checkpoint inhibitor and the antiangiogenic drug may improve clinical response in NSCLC by blocking the accumulation of immunosuppressive cells and promoting influx of effector T cells into tumors.

Pharmacokinetic Comparability of Risankizumab Formulations in Prefilled Syringe and Auto-injector for Subcutaneous Injection

PurposeRisankizumab is a humanized immunoglobulin G1 monoclonal antibody that inhibits the p19 subunit of interleukin 23 from interacting with its receptor for the treatment of moderate to severe plaque psoriasis. The aim of this Phase I biopharmaceutics bridging study was to evaluate the pharmacokinetic comparability, immunogenicity, and tolerability of the risankizumab 90 mg/mL prefilled syringe (PFS) and the risankizumab 150 mg/mL PFS and auto-injector (AI) in healthy subjects. MethodsHealthy subjects received one 150-mg dose of risankizumab in 1 of 3 ways (226 subjects randomized 3:3:1 to 3 treatment arms): 150 mg/mL by PFS × 1 SC injection, 90 mg/mL by PFS × 2 SC injections, or 150 mg/mL by AI × 1 SC injection, and were followed up for 140 days after dosing for the collection of pharmacokinetic, immunogenicity, and tolerability data. FindingsRisankizumab concentration–time profiles overlapped with comparable pharmacokinetic parameters across all treatment arms, indicating similar pharmacokinetic characteristics. The CIs with both formulations and forms of administration were within the bioequivalence range of 0.80–1.25 across all measures of exposure. The prevalence of treatment-emergent anti-drug antibodies and the percentages of subjects who reported at least 1 treatment-emergent adverse event were comparable across all treatment arms. ImplicationsBioequivalence was established between risankizumab 150 mg/mL PFS and 90 mg/mL PFS, and between 150 mg/mL PFS and AI, along with comparable immunogenicity profiles across all 3 treatment arms. Risankizumab 150 mg SC delivered by PFS or AI was well tolerated, with comparable safety profiles across all treatment arms, and no new safety risks were identified.

ROR1 targeting with the antibody-drug conjugate VLS-101 is effective in Richter syndrome patient–derived xenograft mouse models

AbstractRichter syndrome (RS) represents the transformation of chronic lymphocytic leukemia (CLL), typically to an aggressive lymphoma. Treatment options for RS are limited and the disease is often fatal. Receptor tyrosine kinase–like orphan receptor 1 (ROR1) is expressed on CLL cells and other cancers but not on healthy adult tissues, making it an attractive, tumor-specific therapeutic target. VLS-101 is being developed as an antibody-drug conjugate (ADC) for therapy of ROR1-expressing (ROR1+) cancers. VLS-101 comprises UC-961 (a humanized immunoglobulin G1 monoclonal antibody that binds an extracellular epitope of human ROR1), a maleimidocaproyl-valine-citrulline-para-aminobenzoate linker, and the antimicrotubule cytotoxin monomethyl auristatin E (MMAE). VLS-101 binding to ROR1 results in rapid cellular internalization and delivery of MMAE to induce tumor cell death. We studied 4 RS patient-derived xenografts (RS-PDXs) with varying levels of ROR1 expression (11%, 32%, 85%, and 99% of cells). VLS-101 showed no efficacy in the lowest-expressing RS-PDX but induced complete remissions in those with higher levels of ROR1 expression. Responses were maintained during the posttherapy period, particularly after higher VLS-101 doses. In systemic ROR1+ RS-PDXs, VLS-101 dramatically decreased tumor burden in all RS-colonized tissues and significantly prolonged survival. Animals showed no adverse effects or weight loss. Our results confirm ROR1 as a target in RS and demonstrate the therapeutic potential of using an ADC directed toward ROR1 for the treatment of hematological cancers. A phase 1 clinical trial of VLS-101 (NCT03833180) is ongoing in patients with RS and other hematological malignancies.

Can emapalumab be life saving for refractory, recurrent, and progressive cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and Janus kinase inhibitors

Although many potent drugs have been used for cytokine storm, mortality is high for patients with coronavirus disease-2019 (COVID-19), which is followed up in the intensive care unit. Interferons (IFNs) are the major cytokines of the antiviral defense system released from many cell types. However, IFN-γ plays a key role in both primary and secondary cytokine storms. If the cytokine storm is not treated urgently, it will be fatal; therefore, it should be treated immediately. Anakinra, an interleukin-1 (IL-1) antagonist, tocilizumab, an IL-6 antagonist, and Janus kinase (JAK) inhibitors are successfully used in cytokine storm caused by COVID-19. However, sometimes, despite these treatments, the patient's clinical course does not improve. Emapalumab (Eb) is the human immunoglobulin G1 monoclonal antibody and is a potent and noncompetitive antagonist of IFN-γ. Eb can be life saving for cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and JAK inhibitors.

631. Preliminary safety and pharmacokinetic profile of VIR-2482: a monoclonal antibody for the prevention of influenza A illness

BackgroundVIR-2482 is a fully human immunoglobulin G1(IgG) monoclonal antibody (mAb) directed against a highly-conserved epitope in the influenza A hemagglutinin stem region and is in clinical development for the prevention of influenza A illness. The Fc region of VIR-2482 has been modified to provide an extended half-life.MethodsThis is a randomized, placebo-controlled, Phase 1/2 study of VIR-2482 administered intramuscularly (IM) to healthy adult volunteers aged 18-64 years old who have not received a current influenza vaccine. The Phase 1 portion of the study will evaluate the safety, tolerability, pharmacokinetic (PK), and immunogenicity profile of VIR-2482 following single (Part A) or multiple doses (Part B). The Phase 2 study will evaluate the efficacy of VIR-2482 in the prevention of influenza A illness as well as safety, tolerability, and PK. Part A is ongoing and consists of four single dose cohorts (N=25/cohort) randomized (4:1) to a single dose of VIR-2482 or placebo at 60, 300, 1200, or 1800 mg. Safety, tolerability, PK and immunogenicity will be evaluated for at least 52 weeks post-dose.ResultsIn Part A, all 100 subjects received a single dose of VIR-2482 (N=80) or placebo (N=20). Preliminary blinded safety data for all cohorts and PK data for the 300 and 1200 mg cohorts are reported here. Dosing was well tolerated; 6% (6/100) of subjects experienced mild injection site reactions, which generally resolved within 48 hrs. Through 12 weeks post-dosing, the majority (124/126; 98.4%) of adverse events (AEs) were mild to moderate in nature, no serious AEs were reported, and no subjects discontinued due to an AE. Based on available data, exposure (Cmax and AUC) between 300 and 1200 mg of VIR-2482 increased in a dose proportional manner. The PK profile of VIR-2482 is consistent with a half-life extended IgG.ConclusionBased on available data, VIR-2482 has been well tolerated following single IM doses of up to 1800 mg in healthy subjects. The preliminary PK profile of VIR-2482 enables once per season dosing. Overall, these data support initiation of a Phase 2 study to evaluate efficacy of VIR-2482 for the prevention of influenza A illness.DisclosuresJennifer Sager, PharmD, Vir Biotechnology (Employee) David K. Hong, MD, Vir Biotechnology (Employee) Aurelio Bonavia, PhD, Vir Biotechnology (Employee) Lynn Connolly, MD, PhD, Vir Biotechnology (Employee) Deborah Cebrik, PhD, Vir Biotechnology (Independent Contractor) Marie Christine Fanget, MS, Vir Biotechnology (Employee) Erik Mogalian, PharmD, PhD, Vir Biotechnology (Employee)

Nonclinical Safety Assessment of FHTR2163, An Antigen-Binding Fragment Against HTRA1 for the Treatment of Geographic Atrophy.

FHTR2163 is an antigen-binding fragment of a humanized immunoglobulin G1 monoclonal antibody directed against high-temperature requirement A serine peptidase 1 (HTRA1) that is being developed as a potential intravitreal (ITV) treatment for patients with geographic atrophy (GA), an advanced form of dry age-related macular degeneration. The nonclinical toxicology program was designed to assess the safety and tolerability of HTRA1 inhibition following ITV administration of FHTR2163 to support ITV administration in patients with GA. FHTR2163 was well tolerated in a single-dose ITV-administered 8-day toxicity study in cynomolgus monkeys following a 50 µL high (>700 mOsm/kg) osmolality formulation up to 12.5 mg/eye; however, 100 µL (2× 50 µL injections) of a high-osmolality formulation resulted in transient retinal detachment. Repeat-dose ITV administration every 2 weeks of FHTR2163 was well tolerated in 8- and 26-week studies with ITV injection of 100 µL (2× 50 μL) of iso-osmolar formulation up to 15 mg/eye, or 50 µL of the high-osmolality formulation up to 12.5 mg/eye. Observed transient and reversible ocular effects included inflammation and perivascular infiltrates, consistent with an immune response attributed to the administration of heterologous (humanized) protein. Overall, FHTR2163 was well tolerated, and the nonclinical package supported the continued clinical development of FHTR2163 in patients with GA.

AHEAD 3‐45 study design: A global study to evaluate the efficacy and safety of treatment with BAN2401 for 216 weeks in preclinical Alzheimer’s disease with intermediate amyloid (A3 trial) and elevated amyloid (A45 trial)

AbstractBackgroundAβ pathologies occur years prior to cortical tauopathy, neurodegeneration, and clinical symptoms. BAN2401 is a humanized immunoglobulin G1 monoclonal antibody that selectively binds to soluble Aβ aggregated species (oligomers, protofibrils). BAN2401 reduced amyloid on PET and slowed cognitive decline in a Phase 2 study in early symptomatic AD. The AHEAD 3‐45 study will test the safety and efficacy of BAN2401 even earlier in the AD continuum.MethodAHEAD 3‐45 consists of two trials (A3 Trial and A45 Trial) under a single protocol and screening process, common schedule of assessments, and distinct dosing regimens tailored to the baseline amyloid level. The study is a Public‐Private Partnership of the Alzheimer’s Clinical Trial Consortium (ACTC), National Institutes of Health (NIH), and Eisai, Inc. The A3 Trial will enroll cognitively normal individuals (CN) with intermediate amyloid (approximately 20‐40 centiloids), at risk for further amyloid accumulation and development of neurofibrillary tangles on tau PET over four years. Approximately 400 participants will be randomized 1:1 to placebo or BAN2401 infusion—8 weeks of titration followed by 10 mg/kg every four weeks for 216 weeks. The A45 Trial will enroll CN individuals with elevated amyloid, defined as amyloid PET approximately >40 centiloids, at risk for cognitive decline over four years. Approximately 1000 participants will be randomized 1:1 to placebo or BAN2401 infusion—8 weeks of biweekly titration dosing, then 10 mg/kg biweekly induction dosing through 96 weeks to clear aggregated Ab, followed by 10 mg/kg every four weeks maintenance dosing through 216 weeks to prevent reaccumulation of Aβ.ResultLongitudinal cognitive, safety, amyloid and tau PET, MRI and fluid biomarker assessments will be performed. The primary outcome of the A3 Trial is prevention of brain amyloid accumulation by amyloid PET at 216 weeks, with delay of tau PET accumulation as a key secondary outcome. The primary outcome measure of the A45 Trial is the Preclinical Alzheimer’s Disease Cognitive Composite 5 (PACC5) scale at 216 weeks.ConclusionThe AHEAD 3‐45 Study will test whether BAN2401 can prevent the accumulation and spread of Aβ deposition, downstream tau pathology, and cognitive decline in at‐risk cognitively normal individuals prior to significant irreversible neurodegeneration.

13883 Maintenance of response through 136 weeks of long-term continuous risankizumab treatment: An analysis of patients from UltIMMa-1 and UltIMMa-2

Introduction: Risankizumab is a humanized immunoglobulin G1 monoclonal antibody that binds to the p19 subunit and selectively inhibits interleukin-23, a cytokine that plays a key role in the development and maintenance of psoriatic lesions. LIMMitless is a phase 3, single-arm, multicenter, open-label extension (OLE) study to assess the safety and efficacy of risankizumab for maintenance in moderate to severe plaque psoriasis (NCT03047395). This analysis evaluated the proportion of patients who maintained high levels of response (90% improvement in Psoriasis Area and Severity Index [PASI 90]) on risankizumab through 136 weeks of treatment.

Mezagitamab Induces Immunomodulatory Effect in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Background Mezagitamab is a fully human immunoglobulin (Ig) G1 monoclonal antibody with high affinity to CD38 that depletes tumor cells expressing CD38 by antibody- and complement-dependent cytotoxicity. CD38 is a cell surface molecule that is highly expressed on myeloma cells, plasma cells, plasmablasts, and natural killer (NK) cells, and is induced on activated T cells and other suppressor cells including regulatory T (Tregs) and B (Bregs) cells. Data suggest that immune landscape changes in cancer patients and this may correlate with disease stage and clinical outcome. Monitoring specific immune cell subsets could predict treatment responses since certain cell populations either enhance or attenuate the anti-tumor immune response. Method To monitor the immune landscape changes in RRMM patients we developed a mass cytometry panel that measures 39-biomarkers to identify multiple immune cell subsets, including T cells (naïve, memory, effector, regulatory), B cells (naïve, memory, precursors, plasmablasts, regulatory), NK cells, NKT cells, gamma delta T cells, monocytes (classical, non-classical and intermediate), dendritic cells (mDC; myeloid and pDC; plasmacytoid) and basophils. After a robust analytical method validation, we tested cryopreserved peripheral blood and bone marrow mononuclear cells from 19 RRMM patients who received ≥ 3 prior lines of therapy. Patients were administered 300 or 600 mg SC mezagitamab on a QWx8, Q2Wx8 and then Q4Wx until disease progression schedule (NCT03439280). We compared the percent change in immune cell subsets at baseline versus week 4 and week 16. Results CD38 is expressed at different levels on immune cells and sensitivity to depletion by mezagitamab generally correlates positively with the density of expression. CD38 is expressed at high densities on plasmablasts, Bregs, NK-cells, pDC and basophils at baseline and this was associated with reductions in peripheral blood and bone marrow (plasmablasts, 95%, Bregs, 90%, NK-cells, 50%, pDC, 55% and basophils, 40%) at week 4 post treatment. In contrast, no changes occurred in the level of total T-cells and B-cells, which is consistent with low expression of CD38 on most cells of these large populations. Among the insensitive cell types, remaining NK-cells acquired an activated, proliferative and effector phenotype. We observed 60-150% increase in activation (CD69, HLA-DR), 110-200% increase in proliferation (Ki-67), and 40-375% increase in effector (IFN-γ) markers in peripheral blood and bone marrow. Importantly, NK-cells which did not express detectable CD38, also exhibited a similar phenotype possibly by a mechanism independent of CD38. Consistent with these data, the remaining CD4 and CD8 T-cell populations exhibited an activated effector phenotype as observed by 40-200% increase in activation, 60-200% increase in proliferation and 40-90% increase in effector markers in peripheral blood. A potential explanation for this acquisition of activated effector phenotypes could be a reduction in suppressive regulatory lymphocytes. Next, we measured levels of Tregs and Bregs, and observed that Bregs which are CD24hiCD38hi were reduced to 60-90% in peripheral blood and bone marrow. In contrast, total Tregs were reduced by only 5-25% because CD38 expression in Tregs appears as a spectrum where only ~10-20% are CD38+, and thus CD38+ Tregs were reduced more significantly (45-75%), reflecting the selectively of mezagitamab to cells expressing high levels of CD38. CD38+ Tregs are induced in RRMM patients, thus we looked at the phenotype of CD38-, CD38mid, and CD38high -expressing Tregs. We observed higher level of markers that correlate with highly suppressive Tregs such as Granzyme B, Ki-67, CTLA-4 and PD-1 in CD38high Tregs. Accordingly, the total Treg population exhibited a less active phenotype after exposure to mezagitamab, which selectively depleted the highly suppressive CD38+ Tregs. Conclusions Chronic treatment with mezagitamab is immunomodulatory in patients with RRMM, which is associated with reductions in tumor burden, subpopulations of B and T regulatory cells, and characterized by conventional NK and T cells exhibiting an activated, proliferative and effector phenotype. The immune landscape changes observed is consistent with the immunologic concept of converting the tumor microenvironment from cold-to-hot and highlights a key mechanistic effect of mezagitamab. Disclosures Berg: Takeda Pharmaceuticals Inc: Current Employment.

ASP5094, a humanized monoclonal antibody against integrin alpha-9, did not show efficacy in patients with rheumatoid arthritis refractory to methotrexate: results from a phase 2a, randomized, double-blind, placebo-controlled trial

BackgroundRheumatoid arthritis (RA) is a chronic, debilitating autoimmune condition characterized by joint synovial inflammation. Current treatments include methotrexate (MTX), biologic agents, and Janus kinase (JAK) inhibitors. However, these agents are not efficacious in all patients and there are concerns regarding side effects and risk of infection as these treatments target immune-related pathways. Overexpression and activation of integrin alpha-9 (α9) on fibroblast-like synoviocytes are associated with RA disease onset and exacerbation. The humanized immunoglobulin G1 monoclonal antibody ASP5094 was designed to inhibit human α9 and is currently under investigation for the treatment of RA.MethodsThis phase 2a, multicenter, randomized, placebo-controlled, double-blind, parallel-group study (NCT03257852) evaluated the efficacy, safety, and biological activity of intravenous ASP5094 10 mg/kg in patients with moderate to severe RA that was refractory to MTX. Patients received ASP5094 or placebo every 4 weeks for a total of three administrations. Both treatment groups used concomitant MTX. The primary efficacy endpoint was the proportion of patients who responded per American College of Rheumatology 50% improvement using C-reactive protein (ACR50-CRP) after 12 weeks of treatment. Biological activity of ASP5094 was assessed via pharmacokinetics and pharmacodynamics of known downstream effectors of α9. Safety was also assessed.ResultsSixty-six patients were enrolled and randomized to placebo (n = 33) or ASP5094 (n = 33). In the primary efficacy analysis, ACR50-CRP response rates were 6.3% and 18.2% at week 12 in the ASP5094 and placebo groups, respectively; a difference of − 11.9, which was not significant (2-sided P value = 0.258). No trends in ACR50 response rates were observed in subgroups based on demographics or baseline disease characteristics, and no significant differences between placebo and ASP5094 were identified in secondary efficacy or pharmacodynamic endpoints, despite achievement of target serum concentrations of ASP5094. Most treatment-emergent adverse events were mild to moderate in severity, and ASP5094 was considered safe and well tolerated overall.ConclusionAlthough no notable safety signals were observed in this study, ASP5094 was not efficacious in patients with moderate to severe RA with an inadequate response to MTX.Trial registrationClinicalTrials.gov, NCT03257852. Registered on 22 Aug. 2017

A Phase II Study of Glembatumumab Vedotin for Metastatic Uveal Melanoma.

Glembatumumab vedotin (CDX-011, GV) is a fully human Immunoglobulin G2 monoclonal antibody directed against glycoprotein NMB coupled via a peptide linker to monomethyl auristatin E (MMAE), a potent cytotoxic microtubule inhibitor. This phase II study evaluated the overall response rate and safety of GV, glycoprotein NMB (GPNMB) expression, and survival in patients with metastatic uveal melanoma. Eligible patients with metastatic uveal melanoma who had not previously been treated with chemotherapy received GV 1.9 mg/kg every three weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints included GPNMB expression, progression-free survival (PFS), overall survival (OS), and toxicity analysis. GPNMB expression was assessed pre- and post-treatment via immunohistochemistry for patients with available tumor tissue. Out of 35 patients who received treatment, two patients had confirmed partial responses (PRs; 6%), and 18 patients had a stable disease (SD; 51%) as the best objective response. 38% of the patients had stable disease >100 days. The grade 3 or 4 toxicities that occurred in two or more patients were neutropenia, rash, hyponatremia, and vomiting. The median progression-free survival was 3.1 months (95% CI: 1.5–5.6), and the median overall survival was 11.9 months (95% CI 9.0–16.9) in the evaluable study population. GV is well-tolerated in metastatic uveal melanoma. The disease control rate was 57% despite a low objective response rate. Exploratory immune correlation studies are underway to provide insight into target saturation, combination strategies, and antigen release.

Abstract 2143: Profiling exhausted T cells using Vectra® Polaris™multiplex immunofluorescence assay in HNSCC

Abstract Background: Head and neck squamous cell carcinoma (HNSCC) is a cancer with the ability to modulate the immune system to evade detection. It is the sixth most frequently diagnosed cancer with 550,000 new cases and 300,000 lives lost worldwide per year. New treatments for HNSCC are urgently needed as patients continue to experience a high mortality rate and low response to surgery and chemotherapeutic treatments. Part of the reason why HNSCC is difficult to treat is it upregulates the expression of immune-checkpoint signaling molecule TIGIT (T cell immunoreceptor with Ig and ITIM domains) to inhibit T cell activation in vivo. Emerging evidence shows TIGIT overexpression in the CD8+ and CD4+ T cells that infiltrate the tumor cells of HNSCC patients. TIGIT expression is also associated with up-regulation of immune-checkpoint ligands PD-1 (programmed cell death protein 1) and LAG-3 (lymphocyte-activation gene 3 aka CD223), markers of T-cell exhaustion. Altogether, activation of the TIGIT/PD-1/LAG-3 axis correlates with an immunosuppressive microenvironment as well as cancer development and progression. Although there is ample evidence that the upregulation of TIGIT decreases the immune response in HNSCC, only limited studies have been published that address the location, expression and co-expression of TIGIT, LAG-3 and PD-1 in the HNSCC microenvironment. Methods: In this study, we sought to establish a robust report of immune cells in the tissue of patients with HNSCC. Using Vectra Polaris multiplex immunofluorescence (IF) assays, we studied T-cell exhaustion and T-cell expression in HNSCC patient tissue using a total of 9 markers essential in cancer immunology. Sequential tissue sections were stained in two panels of 6, an exhausted T cell panel comprised of TIGIT, PD-1, LAG-3, panCK, CD4 and CD8 and a T cell panel including CD3, FOXP3, CD45RO, panCK, CD4 and CD8. Results: Multiplexing IF staining revealed a HNSCC histologic landscape characteristic of immune suppression in this study. The data demonstrated abundant T cells with TIGIT overexpression in the tissue microenvironment of HNSCC samples. Using Indica Halo algorithms, we quantified exhausted T cells (TIGIT+PD1+LAG3+CD4+CD3+, TIGIT+PD1+LAG3+CD8+CD3+), T helper cells (CD3+CD4+), T cytotoxic cells (CD3+CD8+), T regulatory cells (CD3+CD4+FoxP3), memory T-cells (CD3+CD4+CD45RO) and anergic T-cells (PD1+CD8+) within the tumor and the stromal regions. Conclusion: Currently AB154, a fully humanized immunoglobulin G1 monoclonal antibody targeting human TIGIT is in phase I clinical trials in HNSCC patients and BGB-A1217, an anti-TIGIT monoclonal antibody in combination with anti-PD-1 monoclonal antibody Tislelizumab is in a Phase 1/1b clinical trial in patients with advanced solid tumors. The Vectra Polaris imaging reported in this study identifies T cell composition in the tumor microenvironment of patients facing high mortality. Citation Format: Sara Pollan, Arezoo Hanifi, Mate Nagy, Nicholas Stavrou, Erinn Parnell, Maricel Gozo, Nickolas Attanasio, Josette William, Qingyan Au. Profiling exhausted T cells using Vectra® Polaris™multiplex immunofluorescence assay in HNSCC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2143.

Efficacy and safety of ramucirumab treatment in patients with advanced colorectal cancer: A protocol for systematic review and meta analysis.

Background:vascular endothelial growth factor receptor 2 (VEGFR-2) has an important role in colorectal cancer pathogenesis and progression. The aim of our study is to provide a protocol for assessing the efficacy and safety of ramucirumab (a monoclonal antibody VEGFR-2 antagonist) for the treatment of advanced colorectal cancer.Methods:The systematic review will be reported according to the preferred reporting items for systematic reviews and meta-analyses protocols. Relevant randomized controlled trials were searched from PubMed, Cochrane Library, Web of Science, Excerpt Medica Database, China National Knowledge Infrastructure, and Wanfang Database. Papers in English or Chinese published from their inception to February 2020 will be included without any restrictions.Study selection and data extraction will be performed independently by 2 investigators. The clinical outcomes including overall response rate, complete response rate (disease control rate), overall survival, progression-free survival, quality of life, immune function, and adverse events, were systematically evaluated. Review Manager 5.3 and Stata 14.0 were used for data analysis, and a fixed or random-effect model of meta-analysis will be used depending upon the heterogeneity observed between studies. Subgroup analysis will be carried out depending on the availability of sufficient clinical data.Results and Conclusion:The findings of this systematic review and meta-analysis will be published in a peer-reviewed journal, and provide more evidence-based guidance in clinical practice.PROSPERO registration number:CRD42020165683.

Pharmacologic Characterization of ALD403, a Potent Neutralizing Humanized Monoclonal Antibody Against the Calcitonin Gene-Related Peptide.

ALD403 is a genetically engineered, humanized immunoglobulin G1 monoclonal antibody that inhibits the action of human calcitonin gene-related peptide (CGRP). Clinical trial data indicate that ALD403 is effective as a preventive therapy for migraine and has an acceptable safety profile. For preclinical characterization of ALD403, rabbit antibodies targeting α-CGRP were humanized and modified to eliminate fragment crystallizable (Fc) γ receptor (FcγR) and complement interactions. The ability of ALD403 to inhibit CGRP-induced cAMP production was assessed using a cAMP bioassay (Meso Scale Discovery). The IC50 for inhibition of cAMP release was 434 and 288 pM with the rabbit-human chimera antibody and the humanized ALD403, respectively. ALD403 inhibited α-CGRP binding with an IC50 of 4.7 × 10-11 and 1.2 × 10-10 M for the α-CGRP and AMY1 receptors, respectively. ALD403 did not induce antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity and did not stably interact with any of the FcγR mediating these functions, exhibiting only weak binding to FcγRI. ALD403 significantly lowered capsaicin-induced blood flow responses in rodents at all time points starting at 5 minutes postapplication in a dose-dependent manner. In conclusion, ALD403 is a potent functional ligand inhibitor of α-CGRP‒driven pharmacology. SIGNIFICANCE STATEMENT: α-Calcitonin gene-related peptide blockade by ALD403 was assessed via radiolabeled ligand displacement, in vitro inhibition of cell signaling, and in vivo inhibition of capsaicin-induced vasodilation. Lack of engagement of fragment crystallizable-mediated immune-effector functions by ALD403 was shown.

P069 ONTAMALIMAB, A FULLY HUMAN MONOCLONAL ANTIBODY AGAINST MUCOSAL ADDRESSIN CELL ADHESION MOLECULE-1, PROVIDES SUSTAINED EXPOSURE FOLLOWING LONG-TERM TREATMENT IN PATIENTS WITH ULCERATIVE COLITIS

Ontamalimab is a fully human immunoglobulin G2 monoclonal antibody against mucosal addressin cell adhesion molecule-1 in development for the induction and maintenance of clinical remission in patients with ulcerative colitis (UC). This study aimed to assess the long-term pharmacokinetics (PK) of ontamalimab in patients with UC, and the effects of concomitant medications on PK parameters.

P069 ONTAMALIMAB, A FULLY HUMAN MONOCLONAL ANTIBODY AGAINST MUCOSAL ADDRESSIN CELL ADHESION MOLECULE-1, PROVIDES SUSTAINED EXPOSURE FOLLOWING LONG-TERM TREATMENT IN PATIENTS WITH ULCERATIVE COLITIS

Abstract Introduction Ontamalimab is a fully human immunoglobulin G2 monoclonal antibody against mucosal addressin cell adhesion molecule-1 in development for the induction and maintenance of clinical remission in patients with ulcerative colitis (UC). This study aimed to assess the long-term pharmacokinetics (PK) of ontamalimab in patients with UC, and the effects of concomitant medications on PK parameters. Methods A 12-week induction study (TURANDOT; NCT01620255) was performed to assess the PK, efficacy and safety of ontamalimab (7.5, 22.5, 75 and 225 mg subcutaneous [s.c.] every four weeks [Q4W]) in patients with UC. Individuals who completed the induction study were eligible for enrollment in an open-label extension (OLE) study (TURANDOT II; NCT01771809) to assess the long-term PK, efficacy and safety of ontamalimab (75 or 225 mg s.c. Q4W up to week 72). Population PK analyses were performed using nonlinear mixed-effects modelling. Exposure-response analyses were performed to assess the relationships between minimum concentration (Cmin,ss) of ontamalimab and clinical response, clinical remission and mucosal healing. The effect of concomitant treatments (used for ≥20% of treatment duration) on PK parameters was also evaluated. Results The PK population included 130 (39.8%) women and 197 (60.2%) men, of median age of 40 years. A 1-compartment model with linear elimination adequately described the PK of ontamalimab. Population estimates of apparent clearance (CL/F) and volume of distribution (V/F) were 0.00917 L/h (0.22 L/day) and 7.44 L, respectively. Albumin had a significant effect on the variability of CL/F. Individuals with albumin levels of 30 g/L and 47 g/L are expected to have CL/F values 44% higher and 23% lower, respectively, than a typical patient with an albumin level of 39 g/L. Anti-inflammatory agents affected CL/F, such that CL/F is expected to be 14% higher in patients receiving than not receiving these agents. Other medications including immunosuppressants, steroids and treatments for peptic ulcers and gastroesophageal reflux disease had no effect on CL/F. Weight was the only covariate that significantly affected V/F. The half-life of ontamalimab was 23.4 days. Concentrations of ontamalimab over 72 weeks in the OLE study were consistent with those observed in the 12-week induction study. Ontamalimab Cmin,ss was related to efficacy, such that at week 16 (week 28 in total including induction), patients with higher Cmin,ss values were more likely to have clinical response, clinical remission and mucosal healing than those with lower Cmin,ss. Conclusion The exposure to ontamalimab was sustained following prolonged treatment in patients with UC for up to 72 weeks. Higher ontamalimab exposure was associated with a higher probability of clinical response.

P446 Transcriptional and microbial biomarkers of response to anti-TL1A therapy in ulcerative colitis: the Phase 2a TUSCANY study

Abstract Background Tumour necrosis factor α-like ligand 1A (TL1A) acts as a synergistic cytokine that amplifies pro-inflammatory signals to increase T-cell, natural killer (NK) cell, and innate lymphoid cell production of cytokines, which are thought to be key drivers of inflammatory bowel disease (IBD) and intestinal fibrosis. The recent Phase 2a TUSCANY study demonstrated the efficacy of PF-06480605, a fully human immunoglobulin G1 monoclonal antibody targeting TL1A, in the treatment of participants with moderate to severe active Ulcerative Colitis (UC). Here, we present transcriptomic analysis of intestinal tissue biopsies and metagenomic analysis of the faecal microbiome to further evaluate the treatment effect of PF-06480605. Methods The Phase 2a, open-label, multicentre, single-arm TUSCANY study (NCT02840721) evaluated the safety, tolerability and efficacy of PF-06480605 in participants with moderate to severe UC. Participants received 500 mg intravenous (IV) PF-06480605 every 2 weeks (Q2W) for a total of 7 doses, with a 14-week follow-up period. We performed RNA sequencing of colonic biopsies and metagenomic sequencing (>40 million reads per sample) of faecal samples taken prior to and after 12 weeks of therapy. Differential expression and cell subset deconvolution by CytoReason were used to identify genes and immune cells involved in response to therapy. Differential abundance analyses based on taxonomic profiling was performed using the GOTTCHA metagenome mapping algorithm to discover whether microbial taxa changed in response to treatment. Results Tissue transcriptomic analysis identified a robust inhibition of adaptive (Th1, Th2 and Th17) and innate (macrophage) inflammatory pathways known to be associated with UC pathogenesis and a significant reduction in fibrosis-associated pathways (MMP3, MMP7 and MMP10). Transcriptomic responses were most pronounced in participants achieving endoscopic improvement (Mayo endoscopic subscore of ≤1). A candidate baseline gene signature was predictive of endoscopic improvement (area under the curve [AUC] 0.75; p-value = 0.03). Metagenomic analysis revealed a significant reduction in inflammatory pathobiont species (S. salivarius, S. parasanguinis, and H. parainfluenzae) following treatment. Conclusion These results provide insight into the molecular and microbial mechanisms underlying the efficacy of anti-TL1A therapy for UC. We defined a baseline transcriptomic signature to predict response and a pathobiont treatment signature. These findings may enable the development of precision medicine strategies for anti-TL1A therapy in the treatment of intestinal inflammation.

DOP72 Safety, tolerability and efficacy of anti-TL1A antibody PF-06480605 in treatment of ulcerative colitis: The open-label, multicentre, Phase 2a TUSCANY study

Abstract Background Widespread disruption of the mucosal immune system is central to the pathogenesis of ulcerative colitis (UC). One component, tumour necrosis factor (TNF) α-like ligand 1A (TL1A), is upregulated at the site of active disease in UC. Treatment of preclinical rodent models with anti-TL1A antibodies decreases disease activity, highlighting their therapeutic potential for UC. PF-06480605 is a first-in-class fully human immunoglobulin G1 monoclonal antibody targeting TL1A. Methods The Phase 2a, open-label, multicentre, single-arm TUSCANY study (NCT02840721) evaluated the safety, tolerability and efficacy of PF-06480605 in treatment of moderate to severe UC. Participants received 500 mg intravenous (IV) PF-06480605 every 2 weeks (Q2W) for a total of 7 doses, with a 14-week follow-up period. Primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and endoscopic improvement (EI) (Mayo endoscopic subscore [centrally read] of ≤1 without friability) at Week 14, respectively. Secondary efficacy endpoints included remission (total Mayo score ≤2, with no individual subscore >1) and endoscopic remission (Mayo endoscopic subscore = 0) at Week 14. Transcriptomic profiling on intestinal biopsies was performed. Results Of the 50 participants who received PF-06480605, 42 completed the study. The majority were male (56.0%) and white (96.0%), with a mean age of 40.0 years and prior experience of anti-TNF inhibitors (72.0%). Pancolitis (48.0%) and left-sided colitis (32.0%) were the most common forms of UC at baseline. There were 109 TEAEs, of which 18 were treatment-related. Aside from worsening UC, the most common TEAE by system organ class was arthralgia, which occurred in 6 participants, and 1 was treatment-related. Treatment-emergent serious adverse events were reported in 3 participants, and considered treatment-related in 1 participant (Table 1). No malignancies or deaths were reported. At Week 14, statistically significant EI was observed in 38.2% of participants (Table 2). The proportions of participants achieving remission and endoscopic remission at Week 14 were 24.0% and 10.0%, respectively. Transcriptomic analyses demonstrated normalisation towards a non-inflamed transcriptome in participants with EI. Conclusion PF-06480605 exhibited an acceptable safety and tolerability profile and statistically significant EI in participants with moderate to severe UC. These results warrant further evaluation in subsequent studies.

Fulminant Fournier’s gangrene in a patient with gastric cancer treated with ramucirumab and paclitaxel

Fournier’s gangrene (FG) is an uncommon form of necrotizing fasciitis, localized on the external genital organs, perianal region, and abdominal wall, accompanied by thrombosis of the feeding arteries, leading to gangrene of the skin and subcutaneous tissue, with manifestations of rapid clinical progression and multiple organ failure. Ramucirumab is a recombinant human immunoglobulin G1 monoclonal antibody that binds to the extracellular binding domain of vascular endothelial growth factor receptor-2 (VEGFR-2) and prevents the binding of all VEGFR ligands. The literature describes bevacizumab, aflibercept, and regorafenib associated with FG in patients with colorectal cancer. According to our knowledge this is the first report of FG possibly related to ramucirumab in a patient with gastric cancer. If not recognized in time, it can lead to fatal complications.