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ATOR-4066, a bispecific antibody targeting CD40 and CEACAM5, induces strong myeloid and T cell-dependent tumor immunity and synergizes with PD-1 blockade

Andersson, Hampus LU ; Uddbäck, Ida ; Hermodsson, Tova LU ; Celander, Mona ; Krishna Shetty, Amulya ; Ljung, Lill ; Nilsson, Anneli LU ; Sundstedt, Anette LU ; von Schantz, Laura LU and Varas, Laura A LU , et al. (2025) In Cancer immunology research 13(12). p.1987-2003
Abstract

Despite recent progress within the field of immuno-oncology, immune suppression in the tumor microenvironment, defective antigen presentation, and low levels of tumor-specific T cells are key limitations of current cancer immunotherapies. CD40-targeting immunotherapies hold promises for addressing these limitations across solid tumors. Here, we describe ATOR-4066, a bispecific antibody that targets CD40 and CEACAM5 developed for immunotherapy of cancer using the Neo-X-Prime platform. ATOR-4066 showed potent CEACAM5-dependent activation in vitro with ability to activate intratumoral immune cells from patient derived material. In vivo, ATOR-4066 induced superior anti-tumor activity compared to CD40 mAb in MC38-CEA tumors and cured mice... (More)

Despite recent progress within the field of immuno-oncology, immune suppression in the tumor microenvironment, defective antigen presentation, and low levels of tumor-specific T cells are key limitations of current cancer immunotherapies. CD40-targeting immunotherapies hold promises for addressing these limitations across solid tumors. Here, we describe ATOR-4066, a bispecific antibody that targets CD40 and CEACAM5 developed for immunotherapy of cancer using the Neo-X-Prime platform. ATOR-4066 showed potent CEACAM5-dependent activation in vitro with ability to activate intratumoral immune cells from patient derived material. In vivo, ATOR-4066 induced superior anti-tumor activity compared to CD40 mAb in MC38-CEA tumors and cured mice with well-established tumors with a heterogeneous CEACAM5 expression. Using RNA sequencing, flow cytometry and cytokine analysis, we show that ATOR-4066 promotes immune cell trafficking to tumors and activates both myeloid cells and T cells within the tumor microenvironment, with limited immune activation in the periphery. ATOR-4066 initially induces a T cell-independent anti-tumor response, yet a functional T cell response is critical for long-term tumor control and immunity directed to tumor antigens other than CEACAM5. Finally, we demonstrate that ATOR-4066 synergizes with PD-1 blockade in vitro. In conclusion, these data provide mechanistic evidence for the proposed mode of action and support further development of ATOR-4066 in CEACAM5 expressing cancers.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer immunology research
volume
13
issue
12
pages
31 pages
publisher
American Association for Cancer Research
external identifiers
  • pmid:40928366
ISSN
2326-6074
DOI
10.1158/2326-6066.CIR-25-0075
language
English
LU publication?
yes
id
6f4ddb7b-87ca-4c0a-b933-9bd2e71c4a0e
date added to LUP
2025-10-13 09:15:07
date last changed
2025-12-19 16:18:52
@article{6f4ddb7b-87ca-4c0a-b933-9bd2e71c4a0e,
  abstract     = {{<p>Despite recent progress within the field of immuno-oncology, immune suppression in the tumor microenvironment, defective antigen presentation, and low levels of tumor-specific T cells are key limitations of current cancer immunotherapies. CD40-targeting immunotherapies hold promises for addressing these limitations across solid tumors. Here, we describe ATOR-4066, a bispecific antibody that targets CD40 and CEACAM5 developed for immunotherapy of cancer using the Neo-X-Prime platform. ATOR-4066 showed potent CEACAM5-dependent activation in vitro with ability to activate intratumoral immune cells from patient derived material. In vivo, ATOR-4066 induced superior anti-tumor activity compared to CD40 mAb in MC38-CEA tumors and cured mice with well-established tumors with a heterogeneous CEACAM5 expression. Using RNA sequencing, flow cytometry and cytokine analysis, we show that ATOR-4066 promotes immune cell trafficking to tumors and activates both myeloid cells and T cells within the tumor microenvironment, with limited immune activation in the periphery. ATOR-4066 initially induces a T cell-independent anti-tumor response, yet a functional T cell response is critical for long-term tumor control and immunity directed to tumor antigens other than CEACAM5. Finally, we demonstrate that ATOR-4066 synergizes with PD-1 blockade in vitro. In conclusion, these data provide mechanistic evidence for the proposed mode of action and support further development of ATOR-4066 in CEACAM5 expressing cancers.</p>}},
  author       = {{Andersson, Hampus and Uddbäck, Ida and Hermodsson, Tova and Celander, Mona and Krishna Shetty, Amulya and Ljung, Lill and Nilsson, Anneli and Sundstedt, Anette and von Schantz, Laura and Varas, Laura A and Levin, Mattias and Säll, Anna and Weilguny, Dietmar and Jansson, Kim and Fritzell, Sara and Hägerbrand, Karin and Lindstedt, Malin and Ellmark, Peter}},
  issn         = {{2326-6074}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{12}},
  pages        = {{1987--2003}},
  publisher    = {{American Association for Cancer Research}},
  series       = {{Cancer immunology research}},
  title        = {{ATOR-4066, a bispecific antibody targeting CD40 and CEACAM5, induces strong myeloid and T cell-dependent tumor immunity and synergizes with PD-1 blockade}},
  url          = {{http://dx.doi.org/10.1158/2326-6066.CIR-25-0075}},
  doi          = {{10.1158/2326-6066.CIR-25-0075}},
  volume       = {{13}},
  year         = {{2025}},
}