A FIRST-IN-HUMAN STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF ALTB-268, A NOVEL PSGL-1 AGONISTIC ANTIBODY

A FIRST-IN-HUMAN STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF ALTB-268, A NOVEL PSGL-1 AGONISTIC ANTIBODY | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 12 March 2025 V1 Latest version Share on A FIRST-IN-HUMAN STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF ALTB-268, A NOVEL PSGL-1 AGONISTIC ANTIBODY Authors : Thijs van Iersel 0000-0002-5754-6165 , Jiyun Chen , Devangi Mehta , Simona Reed , Iming Cho , Rhea Rebello , Shih Lin , Daniel Dickerson , Heather Jordan , Christel Westenbroek 0000-0002-8410-6923 , and Jesse Hall [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174176118.89143866/v1 715 views 240 downloads Contents Abstract Introduction Methods Results Discussion Acknowledgements. Contributors Conflict of interest statement. Data availability statement Figure Legends Supplementary Material References Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Aims: ALTB-268 is an agonist antibody targeting the immune checkpoint regulator P-selectin glycoprotein ligand-1 (PSGL 1) to down-regulate pathogenic T-cells. ALTB-268 is a tetravalent antibody and more potent in vitro than ALTB-168 (neihulizumab) which has shown to be efficacious in phase 2 studies for T-cell-mediated autoimmune diseases and acute graft-versus-host disease (GvHD). This dose escalation study evaluated tolerability, safety, pharmacokinetic (PK), and pharmacodynamics (PD) in healthy subjects. Methods: Fifty-six subjects were randomly assigned to single subcutaneous (SC) doses of 25, 75, 225, or 675 mg, or multiple weekly SC doses of 75 mg or 225 mg on Days 1, 8, 15 and 22, or a loading dose of 500 mg on Day 1, followed by doses of 250 mg on the remaining days. Results: No clinically meaningful adverse events (AEs) were observed. Plasma exposure increased more than dose-proportionally after single doses across the entire dose range. After repeated exposure steady-state conditions were reached by Day 29. The level of receptor occupancy (RO) in T-cells showed a clear relationship to dose, with full RO observed after a single 675mg SC dose and after repeated administration of 225 mg SC weekly. Additional doses did not appear to further increase the level of receptor occupancy. Conclusions: ALTB-268 was safe and well-tolerated by healthy subjects. Full and durable RO over the 4-week treatment period was achieved with a loading dose of 500 mg SC followed by weekly dosing with 250 mg SC. These study results support the further clinical development of ALTB-268. Introduction Ulcerative colitis (UC) is a chronic inflammatory disease that affects the colorectal mucosa. It is estimated that up to 90% of patients with UC will have at least one relapse after the first attack and 50% will have at least one relapse per year. About 80% of these relapses are of mild to moderate intensity and about 20% are severe. The pathogenesis of UC is complex and not completely known but accumulating evidence suggests that in genetically predisposed individuals environmental factors contribute to trigger an overly aggressive T-cell-mediated immune-inflammatory response against components of the luminal flora, eventually leading to mucosa damage. In addition to roles in cell trafficking, the adhesion receptor P-selectin glycoprotein ligand-1 (PSGL-1) expression on effector T-cells has been shown to suppress T-cell proliferation 1 , and crosslinking of PSGL-1 induces apoptosis of activated T-cells. 2 By dampening TCR signals, limiting survival of effector T-cells, and promoting immune inhibitory receptor expression, PSGL-1 promotes T‑cell exhaustion. 3 PSGL-1 deficiency increases the severity of animal models of autoimmune diseases, including inflammatory bowel disease 1 . ALTB-268 is a crystallizable fragment (Fc) fusion protein, containing tandem diabodies, creating a tetravalent PSGL-1 agonist antibody (Figure 1). By its mode of action ALTB-268 is acting as an immune checkpoint enhancer which preferentially downregulates late-stage activated T-cells. 2-4 In an in-vitro study, ALTB-268 treatment reduced CD25 expression, interferon (IFN)-γ secretion and proliferation of human activated T-cells. In a dextran sodium sulphate-induced colitis model developed in human PSGL-1 knock-in mice, ALTB-268 ameliorated disease severity as demonstrated by the reduced disease activity index score, the colon weight/length ratio and histological damage of colitis, in addition to the reduced inflammatory cytokines and leukocyte infiltration in the colon. 5 Comparing to the first generation PSGL-1 agonist ALTB-168 (neihulizumab) which has demonstrated promising preliminary Phase 2 results in graft-versus-host-disease, ulcerative colitis and psoriatic arthritis by intravenous (i.v.) administration, tetravalent ALTB-268 is more potent both in vitro and in vivo. 6-8 This increased potency may enable a more patient-friendly subcutaneous (s.c.) dosage administration. Having an immunoglobulin G4 (IgG4) Fc, ALTB-268 did not induce complement-dependent cytotoxicity or antibody-dependent cell-mediated cytotoxicity activity or cell death in neutrophils, B cells, or monocytes and did not activate or impair the function of human platelets in vitro. The objectives of this First-in-Human (FiH) study were to investigate the safety, tolerability pharmacokinetics (PK) and pharmacodynamics (PD) of ALTB‑268 after administration of single and multiple ascending s.c. doses in healthy subjects. Methods Study ethics and design This study was not registered, as Phase 1 studies are exempted from registration set forth in the US Code of Federal Regulations (Title 42 CFR, 2023, §11.22). The study was conducted in compliance with the International Council for Harmonisation (ICH) E6(R2) Guideline for Good Clinical Practice 9 , and applicable national and local laws and regulations. The original protocol and other study related documents were approved by an independent ethics committee. All subjects provided written informed consent prior to the start of study specific procedures. This was a randomised, double-blind, placebo-controlled study. Healthy male or female subjects aged 18 to 55 years, with a body mass index of 18.0 to 32.0 kg/m 2 , were enrolled. Main exclusion criteria included a history of a clinically significant allergy, or a positive QuantiFERON-TB Gold tuberculosis test. Subjects were enrolled in seven different cohorts as summarized in Table 1. In each cohort eight subjects were enrolled, randomised in a 6:2 ratio to receive ALTB‑268 or placebo. This sample size was deemed sufficient to provide information on safety, tolerability, PK, and PD while exposing as few subjects as possible to the investigational product and study procedures. ALTB‑268 or placebo was administered by s.c. bolus injection in the abdomen using a 125 mg/mL formulation. The injections were performed by a separate administration team to keep the randomization blinded. The injections were given in the morning after an overnight fast and subjects remained fasting for one hour after dosing. The PK PD properties of ALTB-268 in humans following s.c. administration were predicted based on PK and PD data of ALTB-268 from cynomolgus monkeys. A single dose of 25 mg was selected a starting dose based on a predicted margin of 3-fold with the Minimum Anticipated Biological Effect Level (MABEL) and a predicted margin of 70-fold with the area under the concentration-time curve (AUC) at the no-observed-adverse-effect level (NOAEL) in monkeys. The pharmacologically active dose (PAD) after single s.c. dosing of ALTB-268 was predicted at 225 mg. The highest planned dose of 675 mg was predicted to result in exposures below the NOAEL exposures as well. Eligible subjects in the single ascending dose (SAD) cohorts had one in-house period consisting of seven nights followed by seven ambulatory visits including the follow-up visit on Day 99. Eligible subjects in the multiple ascending dose (MAD) cohorts had four in-house periods varying in length between one and nine nights, and eight ambulatory visits including the follow-up visit on Day 120. In each single dose cohort, two sentinel subjects (one on active and one on placebo) were dosed at least six days ahead of the other subjects of the cohort. Prior to each dose escalation safety, tolerability and available PK data were assessed. Dose escalation and stopping rules are described in the supplementary material. Safety and tolerability assessments Safety and tolerability assessments consisted of adverse events (AEs), clinical laboratory values, vital signs, 12­lead electrocardiogram (ECG), physical examination, local tolerability, cytokine release, and occurrence of anti-drug-antibodies (ADA). Blood samples for the analysis of ADA were analysed by BioAgilytix in San Diego, CA, USA. The statistical analysis and reporting were done using SAS ® for WindowsTM Version 9.4 (SAS Institute, Inc. NC, US). Pharmacokinetic sample collection, assessments and analysis Plasma samples were collected at pre-defined time points for the determination of ALTB-268 and were analysed using a validated ELISA method by ICON Bioanalytical Laboratories in Lenexa, KS, US. The lower limit of quantification was 50 ng/mL. Plasma PK parameters for ALTB-268 were estimated using non-compartmental methods using Phoenix® WinNonlin ® Version 8.1 (Certara Inc, NJ, USA) using best fit regression. Additional PK computations were performed in SAS®. For Part A, the plasma PK parameters C max , AUC 0-last, and AUC 0-inf for ALTB-268 were compared across each dose level to assess dose proportionality. Statistical analyses were done using a power model. To access the dose proportionality, the 90% confidence interval (CI) of the slope was compared with (1+ln(0.5)/ln(r),1+ln(2)/ln(r)), where r is a ratio that describes the dose range and is defined as the ratio of highest dose/lowest dose. Pharmacodynamic sample collection, assessments and analysis Blood samples were taken for 1) RO by an ex-vivo cell receptor binding assay that evaluated the ability of ALTB-268 to bind to the extracellular domain of the PSGL-1 protein expressed on circulating human T-cells, and 2) immunophenotyping assessments such as measurements of lymphocyte subsets (T, B, and NK cells) and/or T-cell subsets (naïve, memory, activated and/or regulatory T-cells). Both RO and immunophenotyping assessments were performed by Flow Contract Site Laboratory, LCC in Bothel, WA, USA. Exploratory population PK/PD analyses were performed using GraphPad Prism (Version 10.2.3). Plasma ALTB-268 concentrations and PSGL1 RO% in whole blood from all subjects were fitted with a simple Emax model as follows: \(RO\%=\frac{concentration\ X\ 100}{EC50+concentration}\). Results Subjects A total of 56 subjects were enrolled into the study. The study was conducted at the ICON Clinical Pharmacology Unit in Lenexa, US, between December 2022 and October 2023. All subjects in the SAD cohorts completed the study. In the MAD cohorts all but four subjects completed the study. Two subjects in the MAD cohorts who received placebo were early terminations due to withdrawal by one subject and discontinuation due to noncompliance by the other subject. In addition, two subjects did not receive the Day 22 dose of study drug due to a positive COVID‑19 test in one subject and a decreased neutrophil count in the other subject. Subject demographics can be found in Table 2. Safety A summary and overview of AEs is presented in Table 3. ALTB-268 was generally well tolerated. No severe or serious AEs occurred. All TEAEs in the SAD cohorts which were considered at least possibly related to ALTB‑268 administration were classified as mild in severity. There was no apparent trend in the frequency of AEs with respect to dose of ALTB-268 or in comparison to placebo. One AE of abdominal wall pain and one AE of injection site reaction were considered likely or definitely related to the study drug, and occurred in the two highest ALTB‑268 dose groups (Supplementary Table S1). In the MAD cohorts, 12 out of 16 AEs were reported after ALTB-268 500 mg/250 mg (Cohort 7), while only one to two AEs were observed in the other groups. Half of the AEs were considered definitely related to ALTB-268, all concerning local tolerability, and all but one occurring in Cohort 7 (Supplementary Table S2). Fourteen AEs were classified as mild in severity and two were of moderate severity. One of these, anorectal cellulitis, occurred after placebo and the other, neutrophil count decrease, occurred after ALTB-268 administration in Cohort 7. The neutrophil count decrease was considered possibly related to study drug and resulted in discontinuation of study drug due to meeting stopping criteria for individual subjects (see supplementary material for stopping rules). This subject had a baseline neutrophil count of 1.501×10 9 /L, i.e. just above the lower level of the reference range of 1.5×10 9 /L. On Day 21 the subject had a neutrophil count of 1.197×10 9 /L which met the stopping criteria of a neutrophil count of ≤1.5 x 10 9 /L, and the subject was withdrawn from the study before receiving the last dose on Day 22. The neutrophil count of this subject had normalized by Day 59. No clinically relevant changes were observed in clinical laboratory assessments, besides the attenuated neutrophil count, vital signs, ECG, or physical examination. Pharmacokinetics ALTB‑268 semi-log scale concentration-time profiles and PK parameters after a single dose of ALTB‑268 are shown in Figure 2 and Table 4 (linear scale concentration-time profiles can be found in Figure S1 in the supplementary material). Following s.c. administration of ALTB-268, the median t max ranged between 48 hours and 97 hours across all doses. The mean t 1/2 increased with increasing doses from 34 hours after the 25-mg dose to 96 hours after the 675-mg dose. Across the dosing range of 25 mg to 675 mg, the slope of the dose proportionality analysis indicates increases of about 1.6 for peak systemic exposure and 1.7 to 1.9 for the total systemic exposure, AUC 0-inf, and AUC 0‑last , respectively (Table S2 in the supplementary material). Multiple-dose semi-log scale concentration-time profiles and PK parameters are shown in Figure 2 and Table 4 (linear scale concentration-time profiles can be found in Figure S1 in the supplementary material). After administration of ALTB-268 on Day 1, median t max ranged from 72 hours to 96 hours. After repeated exposure steady-state conditions were reached by Day 29. The level of accumulation was higher in the 75 mg dose (6.4-fold for C max and 4.0-fold for AUC) than in the 225 mg cohort (2.0-fold for C max and 2.2-fold for AUC) while there was only minimal accumulation in the 500mg/250 mg cohort. Pharmacodynamics Receptor occupancy PSGL-1 RO on circulating T cells was measured using a validated whole blood flow cytometry assay, with full receptor saturation measured as T-cells showed a pronounced increase during the first 2 days postdose. The maximum mean % RO increased with increasing doses, from 38% after 25 mg ALTB-268 dose to 98.48% after 675 mg ALTB-268. The mean % RO remained fairly stable between Day 2 and Day 5 for the 25-mg, 75-mg, and 225-mg doses, after which the % RO declined reaching baseline levels on Day 38. For the 675-mg dose, the mean % RO level remained relatively stable up to Day 10, after which they declined to just above baseline levels on Day 38 (Figure 3). After the first dose of ALTB-268 in the MAD cohorts, the mean % RO were in the same range as were found in the SAD cohorts for similar (or comparable) doses. The mean % RO remained relatively stable up to Day 26 (four days after the last dose of ALTB-268) for all 3 dose levels, after which it declined to baseline levels on Day 59. Administration of the first 225 mg dose or the 500 mg loading dose of ALTB-268 resulted in similar levels of mean % RO on Day 2, while the % RO remained at the same level for the 225-mg dose, the 500-mg loading dose led to a further increase in the mean % RO on Day 5. Repeat administration of ALTB-268 in the 225 mg or 500/250 mg cohort demonstrated similar mean %RO by the fourth dose where full RO (>80% RO) was achieved over the dosing interval for both cohorts (Figure 3). Immunophenotyping There was no meaningful change among lymphocyte subsets, which included total NK (CD3/CD16+/CD56+), B (CD3-/CD19+), T-helper (CD3+, CD3+/CD4+), and cytotoxic-T-cells (CD3+/CD8+), with ALTB-268 administration as a single or multiple dose regimen. Additionally, no effect of ALTB-268 was observed in the regulatory CD4+ T-cell subset (CD25+/127lo/5+/4+) which was analyzed only in the multiple-dose cohorts. PK PD modelling Figure 4 shows pooled data of plasma ALTB-268 concentrations and PSGL1 RO%, and the fitted simple Emax model. The ALTB-268 plasma concentration predicted to occupy 50% of PSGL1 receptors in whole blood (EC 50 ) was 2370 ng/mL, which equates to a free drug concentration of 20 nM (the molecular weight of ALTB-268 is 150 kDa). Immunogenicity All subjects in Parts A and B were evaluated for ADA using a 3-tiered approach, including screening, confirmation, and titering of ADA responses. The ADA assay is highly sensitive and drug tolerant, and the reported 5 ng/mL sensitivity during assay validation is 20-fold greater than the required sensitivity. 10 As a result, this assay is capable of detecting both clinically relevant and irrelevant ADA responses. In the SAD and MAD, respectively 25% and 12.5% of subjects were confirmed positive for ADAs at baseline (predose). The majority of subjects that were ADA-positive at baseline did not have an increase in titers after treatment. At the subsequent measurements the number of subjects confirmed positive for ADA increased. Of the subjects that were ADA-positive the majority had low titer values (i.e., titer ≤122). Overall, there were no safety findings associated with the presence of ADAs. Preliminary analyses found no apparent impact of ADA status or titer level on PK or PD profiles. Discussion ALTB-268 is a second-generation PSGL-1 agonistic antibody proposed for the treatment of UC that demonstrates increased potency compared to neihulizumab and formulated for convenient SC administration. Results from this FiH study demonstrated that single SC doses up to 675 mg and a SC loading dose of 500 mg with subsequent multiple weekly SC doses of 250 mg ALTB‑268 were safe and well tolerated. The most frequently reported AE in both study parts was headache followed by gastroenteritis in Part A and injection site erythema, injection site induration, and injection site pain in Part B. The majority of AEs reported were considered mild and to be related to the study drug. All AEs resolved by the end of study. For clinical laboratory measurements, vital signs, ECG, and physical examination findings there were no clinically meaningful trends identified, except for the one subject who had a neutrophil count decrease. A limitation of the current study is that it only evaluated the effects of up to four weekly doses of ALTB-268 in healthy subjects. Patients with UC could respond differently, and experience different and additional adverse events after prolonged exposure. Since the target of ALTB-268, PSGL 1, is expressed on nearly all leukocytes, a decrease in neutrophil count below 1.5×10 9 /L was a stopping rule for individual subjects per protocol. One subject in the 3 rd MAD cohort (500 mg/250 mg) had a neutrophil count of 1.197×10 9 /L onDay 21 and was withdrawn from the study before the last planned dose on Day 22. This subject had already borderline low neutrophil counts at Screening and Admission of 1.562×10 9 /L and 1.501×10 9 /L, respectively (reference range 1.5×10 9 /L - 7.8×10 9 /L). This subject was a Black/African American male and his neutrophil count rose to 1.578×10 9 /L at follow-up (Day 59). Although the transient decrease in neutrophil count was considered possibly related to ALTB-268 treatment, it is also possible that this AE may be related to a benign neutropenia phenotype frequently occurring in people identifying as Black or African American. 11 By its mode of action ALTB-268 preferentially downregulates late-stage activated T-cells by inhibiting the T-cell effector function, promoting T-cell exhaustion and apoptosis while sparing resting T-cells and other immune cells. The results from this FiH study with healthy volunteers demonstrated that ALTB-268 did not impact circulating lymphocyte subsets, including CD4+ T helper- and CD8+ cytotoxic T-cells, B and NK cells. Additionally, no meaningful changes were observed on circulating cytokines for any of the doses. As the current study was performed in healthy subjects, with presumably no notable activated T-cells, the lack of effect of ALTB-268 on lymphocyte subsets was expected. This corroborates with in vitro data, where ALTB-268 down-regulates T‑cell proliferation, CD25 expression and IFNγ secretion, and cell viability of activated T-cells, but had no effect on non-activated T-cells. Given the reported expression of PSGL-1 on regulatory T cells, this subset of T cells was evaluated in the current study and no changes in the level of regulatory T cells was observed across all cohorts. This FiH study also characterized the PK, PD and immunogenicity of ALTB-268 administration. After single dose SC administration of ALTB-268, the systemic exposure increased greater than dose proportionally. The slope of the terminal log-linear exposure curve (Figure 2) as well as CL/F (L/h) (Table 4) were decreasing at higher dose levels. This nonlinear pharmacokinetics phenomenon is commonly observed for therapeutic antibodies and is caused by target-mediated drug disposition. 12 It is expected that the half-life of 95.77 h, as observed after a single dose of 675 mg, is near maximal as this dose resulted in near complete RO. The terminal half-lives were in the same order of magnitude for ALTB-268 (225-mg and 675-mg doses) as for neihulizumab (3‑mg/kg and 6‑mg/kg doses) at 56.4 to 95.77 hours, and 72.1 and 116.9 hours, respectively. 13 Following multiple doses of ALTB-268 on Days 1, 8, 15 and 22, steady-state appeared to have been achieved by Day 29 for all doses. After a single administration of ALTB-268, the level of RO in T-cells following ALTB-268 administration showed a clear dose-dependent increase to full RO up to Day 10 following the highest dose of 675 mg. Multiple weekly doses of 225 mg and a loading dose of 500 mg followed by weekly doses of 250 mg resulted in full RO throughout the dose interval by the fourth dose on Day 22. After the last dose, the RO levels slowly declined following the decline of the ALTB-268 plasma concentrations. The PK-PD modelling done by a simple E max model showed a positive correlation between plasma ALTB-268 concentrations and PSGL 1 receptor occupancy in whole blood with the EC 50 estimated at 2370 ng/mL. The % RO in the current study were comparable to the levels found after a single i.v. administration of 3 mg/kg and 6 mg/kg ALTB-168 (225‑mg and 450-mg dose for a subject with a body weight of 75 kg), which were 55.5% and 92.5%, respectively. 13 Overall, an increase was observed in the number of subjects that were ADA-positive after administration of ALTB-268, although without apparent dose relationship, the titers were low, and the increases did not result in AEs and had no apparent impact on PK or RO results. Thus, the observed immunogenicity was likely not clinically relevant. The current study showed that both multiple weekly doses of 225 mg and a loading dose of 500 mg followed by weekly doses of 250 mg was sufficient to reach >80% RO by Day 5. As a tetravalent antibody ALTB-268 demonstrated increased in-vitro potency over the bivalent antibody neihulizumab and thus full RO may not be necessary for ALTB-268 therapeutic efficacy. Therefore, in the current study we have covered the anticipated pharmacological range to evaluate s.c. administration of ALTB-268 in future studies. Acknowledgements. Altrubio has provided funding for the conduct and administration of this study. Altrubio also provided financial support for development of the publication. Contributors J.H., T.v.I., were involved in the design of the study. D.D. was involved in the execution of the study. All authors were involved in drafting and editing the manuscript and approving the final version. Conflict of interest statement. The authors declare no competing financial interests Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical restrictions. TABLE 1 Treatment cohorts. 1 Single dose of 25 mg or placebo. 2 Single dose of 75 mg or placebo. 3 Single dose of 225 mg or placebo. 4 Single dose of 675 mg or placebo. 5 Multiple doses of 75 mg or placebo, on Day 1, 8, 15, and 22. 6 Multiple doses of 225 mg or placebo, on Day 1, 8, 15, and 22. 7 Loading dose of 500 mg or placebo on Day 1 followed by multiple doses of 250 mg or placebo, on Day 8, 15, and 22. TABLE 2 Baseline demographics of enrolled subjects. Demographics Placebo 25 mg 75 mg 225 mg 675 mg Total (N=8) (N=6) (N=6) (N=6) (N=6) (N=32) Age in years a 30.8 (8.8) 33.2 (7.0) 31.8 (6.0) 31.0 (11.3) 45.5 (7.7) 34.2 (9.6) BMI (kg/m 2 ) a 26.6 (2.3) 27.2 (2.0) 25.1 (4.2) 23.0 (2.8) 26.9 (4.0) 25.8 (3.3) Female [n (%)] 0 2 (33.3) 3 (50.0) 2 (33.3) 4 (66.7) 11 (34.4) Male [n (%)] 8 (100.0) 4 (66.7) 3 (50.0) 4 (66.7) 2 (33.3) 21 (65.6) Ethnicity [n (%)] Hispanic or Latino 1 (12.5) 0 0 0 1 (16.7) 2 (6.3) Not Hispanic or Latino 7 (87.5) 6 (100.0) 6 (100.0) 6 (100.0) 5 (83.3) 30 (93.8) Race [n (%)] White 5 (62.5) 2 (33.3) 5 (83.3) 5 (83.3) 4 (66.7) 21 (65.6) Black or African American 1 (12.5) 4 (66.7) 1 (16.7) 1 (16.7) 2 (33.3) 9 (28.1) Asian 1 (12.5) 0 0 0 0 1 (3.1) Other 1 (12.5) 0 0 0 0 1 (3.1) MAD Part ALTB-268 ALTB-268 ALTB-268 Demographics Placebo 75 mg 225 mg 500 mg /250mg* Total (N=6) (N=6) (N=6) (N=6) (N=24) Age in years a 42.7 (1.37) 40.7 (7.09) 41.5 (9.69) 35.0 (2.28) 40.0 (6.48) BMI (kg/m 2 ) a 25.2 (4.54) 26.5 (4.2) 26.3 (2.1) 27.0 (3.4) 26.2 (3.5) Female [n (%)] 4 (66.7) 2 (33.3) 4 (66.7) 2 (33.3) 12 (50.0) Male [n (%)] 2 (33.3) 4 (66.7) 2 (33.3) 4 (66.7) 12 (50.0) Ethnicity [n (%)] Hispanic or Latino 2 (33.3) 1 (16.7) 0 0 3 (12.5) Not Hispanic or Latino 4 (66.7) 5 (83.3) 6 (100.0) 6 (100.0) 21 (87.5) Race [n (%)] White 3 (50.0) 6 (100.0) 3 (50.0) 3 (50.0) 15 (62.5) Black or African American 2 (33.3) 0 3 (50.0) 3 (50.0) 8 (33.3) Other 1 (16.7) 0 0 0 1 (4.2) Abbreviations: BMI, body mass index; MAD, multiple ascending dose; N, number of subjects; n, number of observations; SAD, single ascending dose. * 500 mg loading dose on Day 1, followed by 250 mg on Days 8, 15, and 22. a Data on age and BMI are mean ± standard deviation. TABLE 3 Summary of adverse events Ear Pain 1 (16.7) 1 (3.1) Abdominal Wall Pain 1 (16.7) 1 (3.1) Nausea 1 (16.7) 1 (3.1) Injection Site reaction 1 (16.7) 1 (3.1) Gastroenteritis 1 (16.7) 1 (16.7) 2 (6.3) Pharyngitis streptococcal 1 (16.7) 1 (3.1) Upper respiratory tract infection 1 (16.7) 1 (3.1) Foot fracture 1 (16.7) 1 (3.1) Decreased appetite 1 (16.7) 1 (3.1) Headache 1 (16.7) 1 (16.7) 1 (16.7) 3 (9.4) Anxiety 1 (16.7) 1 (3.1) Epistaxis 1 (16.7) 1 (3.1) Urticaria 1 (16.7) 1 (3.1) MAD Part Preferred term Placebo (N=6) n (%) ALTB-268 75 mg (N=6) n (%) ALTB-268 225 mg (N=6) n (%) ALTB-268 500 mg/250 mg* (N=6) n (%) Total (N=24) n (%) Injection site erythema 2 (33.3) 2 (8.3) Injection site induration 2 (33.3) 2 (8.3) Injection site pain 2 (33.3) 2 (8.3) Pyrexia 1 (16.7) 1 (4.2) Injection site reaction 1 (16.7) 1 (4.2) anorectal cellulitis 1 (16.7) 1 (4.2) viral infection 1 (16.7) 1 (4.2) neutrophil count decreased 1 (16.7) 1 (4.2) SARS-CoV-2 test positive 1 (16.7) 1 (4.2) headache 1 (16.7) 2 (33.3) 3 (12.5) Abbreviations: SAD, single ascending dose; MAD, multiple ascending dose; N, number of subjects; n, number of subjects that experienced the AEs. * 500 mg loading dose on Day 1, followed by 250 mg on Days 8, 15, and 22. TABLE 4 ALTB-268 plasma pharmacokinetic parameters. C max (ng/mL) 291 (67.9) 1700 (42.0) 11100 (26.8) 37000 (22.5) t max (h) 48 (24,48) 71 (48, 71) 97 (73, 98) 84 (48, 145) AUC 0-last (h•ng/mL) 24000 (77.8) 238000 (53.4) 1950000 (28.8) 9470000 (12.8) AUC 0-inf (h•ng/mL) 43300 (38.0) 248000 (52.2) 2000000 (28.1) 9490000 (12.9) t 1/2 (h) 34.04 (21.2) a 42.30 (20.3) 56.40 (15.4) 95.77 (20.5) CL/F (L/h) 0.652 (45.8) a 0.374 (46.6) 0.123 (38.5) 0.0240 (12.1) Vz/F (L) 32.1 (46.7) a 21.4 (33.5) 9.93 (36.5) 3.34 (27.0) Part B (MAD) Day PK Parameter ALTB-268 75 mg Mean (CV%) (N=6) ALTB-268 225 mg Mean (CV%) (N=6) ALTB-268 500 mg/250 mg Mean (CV%) (N=6) Day 1 C max (ng/mL) 1810 (81.7) 11900 (30.1) 28900 (51.7) t max (h) 96 (72, 120) 72 (48, 96) 84 (48, 120) AUC 0-168 (h•ng/mL) 214000 (85.7) 1440000 (29.2) 3380000 (46.1) Day 8 C trough (ng/mL) 924 (107) 6640 (28.6) 17100 (23.7) Day 15 C trough (ng/mL) 1750 (94.9) 10200 (23.3) 16800 (24.5) Day 22 C max (ng/mL) 4780 (47.6) 22700 (22.4) 33000 (10.9) b t max (h) 72 (24.00, 96.00 48 (48, 72) 60 (48, 72) b AUC 0-tau (h•ng/mL) 543000 (68.7) 3000000 (20.6) 4610000 (16.7) b C trough (ng/mL) 2290 (86.8) 13900 (19.9) 22100 (21.6) c R ac C max 6.38 (136) 1.96 (15.7) 1.12 (36.3) b R ac AUC 4.02 (65.0) 2.16 (22.3) 1.34 (39.2) b Day 29 C trough (ng/mL) 2240 (97.1) 14400 (27.0) 18300 (49.8) Abbreviations: AUC, area under the concentration-time curve; C max , peak plasma concentration; C trough , predose plasma concentration; CV, coefficient of variation; MAD, multiple ascending dose; N=number of subjects exposed, n, number of subjects; PK, pharmacokinetics; R ac , ration of accumulation; SAD, single ascending dose; t max , time of peak concentration. Data presented are arithmetic mean (CV) for all parameters except for t max, which are median (minimum, maximum). a n=3 b n=4 c n=5 Figure Legends Figure 1 Schematic of ALTB-268 structure. fusion protein of IgG4 Fc (grey) linked to four tandem agonist diabodies (blue) targeting PSGL-1. Abbreviations: Fc, crystallizable fragment; IgG4,Immunoglobulin G4; PSGL-1, P-selectin glycoprotein ligand-1 Figure 2 Mean (± SD) concentration vs. time profiles of ALTB-268 (semi-log scale). Abbreviations: SAD, single ascending dose; MAD, multiple ascending dose; SD, standard deviation. Figure 3 Mean (± SD ) Receptor Occupancy vs. time profiles of ALTB-268. Abbreviations: SD Standard deviation; SAD, single ascending dose; MAD, multiple ascending dose. Figure 4 Relationship between ALTB-268 plasma exposure and PSGL1 receptor occupancy in whole blood. Abbreviations: EC50, half maximum effective concentrations; RO, receptor occupancy Supplementary Material File (figure 1.docx) Download 29.68 KB File (figure 2.docx) Download 233.30 KB File (figure 3.docx) Download 224.58 KB File (figure 4.docx) Download 31.54 KB References 1. Matsumoto M, Miyasaka M, Hirata T, P-selectin glycoprotein ligand-1 negatively regulates T-cell immune responses, J Immunol, 2009; 183: 7204-7211. Google Scholar 2. Chen SC, Huang CC, Chien CL, Jeng CJ, Su HT, Chiang E, Liu MR, Wu CH, Chang CN, Lin RH, Cross-linking of P-selectin glycoprotein ligand-1 induces death of activated T cells, Blood, 2004; 104: 3233-3242. Google Scholar 3. Tinoco R, Carrette F, Barraza ML, Otero DC, Magaña J, Bosenberg MW, Swain SL, Bradley LM, PSGL-1 Is an Immune Checkpoint Regulator that Promotes T Cell Exhaustion, Immunity, 2016; 44: 1190-1203. Google Scholar 4. 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Keywords drug development immunology pharmacodynamics pharmacokinetic-pharmacodynamic pharmacokinetics phase i Authors Affiliations Thijs van Iersel 0000-0002-5754-6165 ICON plc View all articles by this author Jiyun Chen Altrubio Inc View all articles by this author Devangi Mehta Immunologix Laboratories View all articles by this author Simona Reed Altrubio Inc View all articles by this author Iming Cho Altrubio Inc View all articles by this author Rhea Rebello Altrubio Inc View all articles by this author Shih Lin Altrubio Inc View all articles by this author Daniel Dickerson ICON plc View all articles by this author Heather Jordan ICON plc View all articles by this author Christel Westenbroek 0000-0002-8410-6923 ICON plc View all articles by this author Jesse Hall [email protected] Altrubio Inc View all articles by this author Metrics & Citations Metrics Article Usage 715 views 240 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Thijs van Iersel, Jiyun Chen, Devangi Mehta, et al. A FIRST-IN-HUMAN STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF ALTB-268, A NOVEL PSGL-1 AGONISTIC ANTIBODY. Authorea . 12 March 2025. DOI: https://doi.org/10.22541/au.174176118.89143866/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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