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First-in-human study of intravenous bispecific CTLA-4 × OX40 antibody (ATOR-1015) in advanced solid malignancies

Ekström-Rydén, V. ; Carneiro, A. LU orcid ; Yachnin, J. ; Staal Rohrberg, K. ; Enell Smith, K. LU ; Ellmark, P. LU orcid ; Løvendahl Eefsen, R. and Ullenhag, G. J. (2026) In ESMO Open 11(5).
Abstract

Background: Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), was the first approved checkpoint inhibitor; however, its use is hampered by treatment-related adverse events (TRAEs). ATOR-1015 is a bispecific antibody targeting CTLA-4 and OX40 designed to direct the effect to the tumor microenvironment and thereby improve the response rate and reduce TRAEs. Materials and methods: We conducted a phase I, first-in-human, multicenter study to determine the safety and tolerability of intravenously administered ATOR-1015 every second week. Secondary objectives were efficacy and pharmacokinetics. An exploratory objective was to investigate the pharmacodynamic effects on the immune system.... (More)

Background: Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), was the first approved checkpoint inhibitor; however, its use is hampered by treatment-related adverse events (TRAEs). ATOR-1015 is a bispecific antibody targeting CTLA-4 and OX40 designed to direct the effect to the tumor microenvironment and thereby improve the response rate and reduce TRAEs. Materials and methods: We conducted a phase I, first-in-human, multicenter study to determine the safety and tolerability of intravenously administered ATOR-1015 every second week. Secondary objectives were efficacy and pharmacokinetics. An exploratory objective was to investigate the pharmacodynamic effects on the immune system. Twenty-eight patients with advanced solid cancer were treated in the last line with ATOR-1015. A modified 3 + 3 dose-escalation design was applied. Results: The most common TRAEs were infusion-related reactions (IRRs) (n = 14, 50.0%), pyrexia (n = 3, 10.7%), myalgia (n = 3, 10.7%) and rash (n = 3, 10.7%). One serious AE occurred (grade III IRR). Best response (according to immune RECIST) was stable disease (n = 11, 39.3%), which lasted >4 months in six patients (21.4%). These patients showed a significant increase in inducible T-cell costimulator-expressing CD4+ and CD8+ central memory T cells 4 h after infusion. In all patients, temporary elevations in absolute lymphocyte count, B cells and T cells as well as interleukin-8, interferon-γ and tumor necrosis factor-α were observed. Conclusions: Although considered safe, the treatment induced neutralizing anti-drug antibodies in most patients, leading to IRRs and reduced efficacy due to low serum exposure, an effect that could not be overcome by increasing doses. Future development requires re-engineering the therapeutic format to minimize immunogenicity, thereby improving both safety and effectiveness.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
bispecific antibody, CTLA-4, metastatic cancer, OX-40, phase I study
in
ESMO Open
volume
11
issue
5
article number
106068
pages
10 pages
publisher
BMJ Publishing Group
external identifiers
  • scopus:105036289692
  • pmid:42019086
ISSN
2059-7029
DOI
10.1016/j.esmoop.2026.106068
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2026 The Author(s)
id
cbf01768-ddbd-40bd-9d18-9de9c73a3b8e
date added to LUP
2026-04-30 13:46:08
date last changed
2026-05-28 15:40:59
@article{cbf01768-ddbd-40bd-9d18-9de9c73a3b8e,
  abstract     = {{<p>Background: Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), was the first approved checkpoint inhibitor; however, its use is hampered by treatment-related adverse events (TRAEs). ATOR-1015 is a bispecific antibody targeting CTLA-4 and OX40 designed to direct the effect to the tumor microenvironment and thereby improve the response rate and reduce TRAEs. Materials and methods: We conducted a phase I, first-in-human, multicenter study to determine the safety and tolerability of intravenously administered ATOR-1015 every second week. Secondary objectives were efficacy and pharmacokinetics. An exploratory objective was to investigate the pharmacodynamic effects on the immune system. Twenty-eight patients with advanced solid cancer were treated in the last line with ATOR-1015. A modified 3 + 3 dose-escalation design was applied. Results: The most common TRAEs were infusion-related reactions (IRRs) (n = 14, 50.0%), pyrexia (n = 3, 10.7%), myalgia (n = 3, 10.7%) and rash (n = 3, 10.7%). One serious AE occurred (grade III IRR). Best response (according to immune RECIST) was stable disease (n = 11, 39.3%), which lasted &gt;4 months in six patients (21.4%). These patients showed a significant increase in inducible T-cell costimulator-expressing CD4+ and CD8+ central memory T cells 4 h after infusion. In all patients, temporary elevations in absolute lymphocyte count, B cells and T cells as well as interleukin-8, interferon-γ and tumor necrosis factor-α were observed. Conclusions: Although considered safe, the treatment induced neutralizing anti-drug antibodies in most patients, leading to IRRs and reduced efficacy due to low serum exposure, an effect that could not be overcome by increasing doses. Future development requires re-engineering the therapeutic format to minimize immunogenicity, thereby improving both safety and effectiveness.</p>}},
  author       = {{Ekström-Rydén, V. and Carneiro, A. and Yachnin, J. and Staal Rohrberg, K. and Enell Smith, K. and Ellmark, P. and Løvendahl Eefsen, R. and Ullenhag, G. J.}},
  issn         = {{2059-7029}},
  keywords     = {{bispecific antibody; CTLA-4; metastatic cancer; OX-40; phase I study}},
  language     = {{eng}},
  number       = {{5}},
  publisher    = {{BMJ Publishing Group}},
  series       = {{ESMO Open}},
  title        = {{First-in-human study of intravenous bispecific CTLA-4 × OX40 antibody (ATOR-1015) in advanced solid malignancies}},
  url          = {{http://dx.doi.org/10.1016/j.esmoop.2026.106068}},
  doi          = {{10.1016/j.esmoop.2026.106068}},
  volume       = {{11}},
  year         = {{2026}},
}