Author: Valentina Fiori

Immune checkpoint inhibitors have transformed cancer therapy, offering durable clinical benefits in several advanced tumors. However, important limitations still affect their efficacy, including resistance mechanisms, variability in patient response, and immune-related adverse events. These challenges continue to drive the need for new immune checkpoint targets and more effective therapeutic strategies.

Within this context, CEACAM1 (Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1) has emerged as a promising next-generation target. It is overexpressed across multiple solid tumors and is strongly associated with tumor invasiveness and metastatic progression. From a biological perspective, CEACAM1 plays a key role in tumor immune escape, suppressing NK and T-cell mediated cytotoxic activity through both homophilic and heterophilic interactions. These mechanisms make it a critical regulator of antitumor immunity and a strategic point of intervention.

Developing a targeted anti-CEACAM1 monoclonal antibody

Building on this scientific rationale, the research team has developed a proprietary monoclonal antibody targeting CEACAM1, an emerging immune therapeutic target
with expression across numerous solid tumor types and correlation with disease invasiveness.

The anti-CEACAM1 program led to the identification of DIA-12.3, a fully human IgG1 monoclonal antibody targeting CEACAM1-expressing tumor cells.

Its development followed a structured process:

  • isolation of a scFv from a human phage display library
  • reformatting into a fully human IgG1 monoclonal antibody
  • development of a stable CHO cell line expressing the DIA-12.3 clone

 

Alongside the main candidate, the team engineered an Fc-silent variant (N297A), designed to reduce effector functions and better understand the underlying mechanisms of action.

A key outcome of this work is the antibody’s specificity. Immunohistochemistry analyses performed by the team show:

  • selective recognition of melanoma and lung carcinoma tissues
  • no significant cross-reactivity in normal adult tissues

 

This level of selectivity supports a highly targeted therapeutic profile.

Preclinical evidence: restoring immune activity

Preclinical in vitro studies highlight the functional potential of DIA-12.3 across multiple tumor models. The antibody demonstrates the ability to:

  • bind efficiently to CEACAM1-expressing metastatic tumor cells
  • enhance NK cell-mediated cytotoxicity
  • stimulate T lymphocytes
  • avoid neutrophil activation, suggesting controlled immune modulation

 

 

These findings reflect a mechanism of action focused on restoring immune activity. In vivo studies using humanized CD34+ mouse models are also giving promising results in PDX and CDX models with significant tumor growth inhibition as a standalone treatment and improved outcomes when combined with anti-PD-1 therapy (pembrolizumab)

From research to clinical potential

The data generated so far point to a candidate with a well-defined and differentiated profile. Key characteristics include:

  • fully human IgG1 structure, supporting low immunogenicity
  • high affinity for the CEACAM1 N-terminal domain
  • selective targeting of tumor tissues
  • ability to restore immune function without excessive activation
  • efficacy both as monotherapy and in combination strategies

 

Advancing this work toward clinical application is the natural next step. Efforts are currently focused on building strategic partnerships and accelerating the transition of DIA-12.3 into Phase I clinical trials, with the aim of bringing a new immune checkpoint strategy closer to patients.

 

Valentina Fiori holds a PhD in Biochemical and Pharmacological Sciences, and is Biologics R&D Manager at Diatheva, where she leads the development of therapeutic recombinant monoclonal antibodies targeting oncology and infectious diseases. She combines scientific strategy with industrial collaboration, managing complex R&D programs that bridge academic innovation and biopharmaceutical application.

 

References:

Dupuis ML, Fiori V, Soriani A et al. J Immunother (2015) 38 (9), 357-370

Centonze M, Fiori V, Kujawski M et al. PLoS One. 2024 Feb 12;19(2):e0295345