Solutions

Online Inquiry

Global Services. (Creative Biolabs Authorized)

CellRapeutics™ Orthogonal Cytokine-Receptor Pair Construction Service

Online Inquiry

Background Features Service Workflow What We Can Offer Highlights FAQs Data support

Background

Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a transformative approach in cancer immunotherapy, showing remarkable efficacy in hematologic malignancies. However, the broader application of CAR T cells to solid tumors and other challenging malignancies remains limited by technical and physiological barriers, such as the need for conditioning chemotherapy and associated toxicities. An innovative solution to overcome these limitations is the use of engineered orthogonal cytokine-receptor pairs, which selectively enhance T cell proliferation and functionality without the unwanted side effects seen with traditional cytokines. Creative Biolabs is at the forefront of this cutting-edge technology, providing industry-leading services in the construction of orthogonal cytokine-receptor pairs for CAR T-cell development.

Features of Orthogonal Cytokine-Receptor Pairs

Molecular Engineering and Specificity

Orthogonal cytokine-receptor pairs are specifically designed to interact with each other using molecular engineering techniques that involve amino acid substitutions. These engineered pairs transmit native cytokine signals but do not interact with their natural counterparts, thereby enabling selective stimulation of targeted cells in vivo. For instance, a human orthogonal IL-2 (ortho-hIL-2) and orthogonal IL-2Rβ (ortho-hIL-2Rβ) pair has been shown to selectively drive the proliferation of ortho-hIL-2Rβ expressing cells. Through this specific interaction, orthogonal cytokines can deliver potent signaling while minimizing off-target effects and toxicities.

Enhanced Proliferation and Functionality

Orthogonal cytokine-receptor systems have been demonstrated to significantly enhance both the expansion and antitumor efficacy of CAR T cells. In murine models, ortho-hIL-2 was able to rescue the anti-leukemic effect of suboptimal CAR T cell doses and even reignite a failed anti-leukemic response. By selectively expanding T cells that express the orthogonal receptor, this platform bypasses the competitive inhibition posed by naturally occurring cytokines, leading to more robust and sustained therapeutic responses.

Our Orthogonal Cytokine-Receptor Pairs Construction Services for CAR T Development

Custom Design and Construction

At Creative Biolabs, we offer bespoke construction services for orthogonal cytokine-receptor pairs tailored to the specific needs of your CAR T-cell development project. Our expertise in protein engineering allows us to create orthogonal cytokine-receptor pairs such as ortho-hIL-2/ortho-hIL-2Rβ, which can significantly reduce your CART design and construction time.

State-of-the-Art Laboratory Capabilities

Our state-of-the-art facilities are equipped with the latest technologies in molecular biology, protein engineering, and cellular immunotherapy. We utilize advanced structure-based protein engineering and combinatorial libraries to create orthogonal pairs with high specificity and efficacy. Our standardized production protocols ensure consistent quality and reproducibility, facilitating smooth translational processes from bench to bedside.

Preclinical Evaluation

We provide comprehensive services that extend beyond molecular construction to include in vitro testing, preclinical evaluation, and professional support. Our rigorous protocols allow for the detailed characterization of the engineered T cells, ensuring they meet the highest standards of safety and efficacy.

What We Can Offer

Binding & Orthogonality	Cell Signaling & Functional Response
Surface Plasmon Resonance or Biolayer Interferometry Competition binding assays Biophysical stability/folding/expression quality	Reporter assays Flow cytometry Proliferation/cell expansion assays Cytokine secretion & multiplex assays
In Vivo / Translational Studies	Safety / Immunogenicity / QC
Animal models (murine, humanized) Pharmacokinetics/pharmacodynamics (PK/PD) Tissue biodistribution, histology, and immunophenotyping	Immunogenicity prediction In vitro immunogenicity assays Toxicity testing in vivo

Discover how we can help - Request a consultation.

How to Work

Workflow of orthogonal cytokine-receptor pairs construction. (Creative Biolabs Original)

Key Advantages

Customized Modular Design: Full flexibility in orthogonal pair design: extracellular (ligand-binding) & intracellular (signaling) domains selection (e.g., IL-2R/7R/15R-derived or chimeric fusions) for precise T-cell fate control.
Synthetic Protein Engineering Expertise: Advanced structure-based/directed evolution techniques to construct orthogonal cytokine-receptor pairs with zero cross-reactivity to native/endogenous ligands.
One-Stop System Delivery: Integrated service: gene design, vector construction, orthogonal ligand protein production, in vitro functional validation - minimizing multi-vendor needs and ensuring system compatibility.

FAQ

How does the orthogonal system enhance CAR-T safety vs. traditional methods?

Eliminates bystander activation. Engineered cells respond only to synthetic cytokine ligand, preventing non-specific native immune cell activation that causes CRS. Full control over survival/proliferation signals; tailor signal strength for safety windows.

What specificity for constructed orthogonal receptor pairs?

Rigorous design/validation ensures complete decoupling. Confirmed zero cross-reactivity between orthogonal cytokine & native receptors, and native cytokines & engineered receptors. Enables precise dosing, minimal off-target effects.

Applicable to immune cells beyond T cells?

Yes. Modular tech allows stable transduction into NK, NKT, and Tregs. Intracellular signaling domains tailored to target cell biology/outcomes. Discuss non-T cell projects with our team.

Scientific Case Backing

Orthogonal IL-2/IL-2Rβ System Stimulate the Expansion of Treg Cells

An application of orthogonal cytokine-receptor pairs involves the selective expansion of regulatory T cells (Tregs), which are critical for the induction of transplantation tolerance. By introducing an orthogonal IL-2Rβ into Tregs, researchers have shown that ortho-IL-2 administration significantly promotes the proliferation of these cells, leading to improved donor hematopoietic cell engraftment and acceptance of organ transplants in murine models. This selective expansion avoids the common pitfall of non-specific activation of other immune cells, thereby enhancing the specific immunosuppressive functions of Tregs.

Fig.1 Application of Orthogonal IL-2/IL-2 receptor system for organ transplantation. (Hirai, Toshihito, et al., 2021) Fig.1 Schematic diagram of orthogonal IL-2/IL-2 receptor system application for organ transplantation.¹

Chimeric Receptor Signaling for Enhanced Antitumor Activity

Synthetic receptor signaling has also been explored by designing chimeric receptors that combine the orthogonal IL-2 receptor extracellular domain (ECD) with the intracellular domain (ICD) of other γc cytokines like IL-9. These chimeric receptors reroute IL-2 signaling to elicit IL-9R-specific responses, thereby enhancing the anti-tumor activities of T cells. In models of melanoma and pancreatic cancer, T cells signaling through the chimeric orthogonal IL-2Rβ-ECD–IL-9R-ICD (o9R) displayed superior antitumor efficacy compared to traditional methods. This approach has immense potential, particularly for solid tumors that have been refractory to previous immunotherapy strategies.

Fig.2 Superior effector function using Orthogonal IL-2Rβ-ECD–IL-9R-ICD constructs. (Kalbasi, Anusha, et al., 2022) Fig.2 Orthogonal IL-2Rβ-ECD–IL-9R-ICD showed superior effector function in TCR- and CAR-engineered T cells.²

Creative Biolabs offers unparalleled expertise in the construction strategies of orthogonal cytokine-receptor pairs, providing a sophisticated toolkit for enhancing the efficacy of CAR T-cell therapies. If you would like to know more about our services, please feel free to contact our technical team.

References

Hirai, Toshihito, et al. "Selective expansion of regulatory T cells using an orthogonal IL-2/IL-2 receptor system facilitates transplantation tolerance." The Journal of clinical investigation 131.8 (2021).
Kalbasi, Anusha, et al. "Potentiating adoptive cell therapy using synthetic IL-9 receptors." Nature 607.7918 (2022): 360-365.

All products and services are For Research Use Only and CANNOT be used in the treatment or diagnosis of disease.