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Murine Model of CD40-activation of B cells
Published on: March 5, 2010
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A Multispecific Anti-CD40 DARPin Construct Induces Tumor-Selective CD40 Activation and Tumor Regression.
Nicolò Rigamonti1, Niina Veitonmäki1, Clara Domke1
1Molecular Partners AG, Zurich-Schlieren, Switzerland.
Cancer Immunology Research
|March 23, 2022
Summary
A novel bispecific antibody construct, α-FAPxCD40, targets cancer by conditionally activating CD40 receptors only at the tumor site. This approach eradicates tumors and induces immune memory, avoiding systemic toxicities seen with traditional CD40 therapies.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- CD40 receptor activation is a promising strategy for cancer immunotherapy.
- Systemic administration of CD40-targeting monoclonal antibodies (mAbs) has a limited therapeutic window, causing toxicity and suboptimal clinical responses.
- Fibroblast activation protein (FAP) is overexpressed in solid tumor stroma, presenting a potential target for localized drug delivery.
Purpose of the Study:
- To develop a novel multispecific DARPin construct, α-FAPxCD40, for conditional CD40 activation at the tumor site.
- To evaluate the in vitro and in vivo efficacy and safety of α-FAPxCD40 in preclinical cancer models.
- To assess the potential of α-FAPxCD40 to overcome the limitations of systemic CD40 activation in cancer immunotherapy.
Main Methods:
- Development of a multispecific DARPin construct (α-FAPxCD40) that binds to both CD40 and FAP.
- In vitro assessment of α-FAPxCD40-mediated activation of antigen-presenting cells in the presence and absence of FAP-positive cells.
- In vivo studies using a murine surrogate construct (α-mFAPxCD40) in FAP-positive tumor models to evaluate tumor rejection, immune memory, and systemic toxicity.
Main Results:
- α-FAPxCD40 demonstrated potent, FAP-dependent activation of human antigen-presenting cells in vitro.
- The murine surrogate construct α-mFAPxCD40 led to the rejection of 88% of FAP-positive tumors and induced antitumor memory immunity.
- In vivo administration of α-mFAPxCD40 did not result in elevated blood cytokines or hepatotoxicity, unlike control anti-CD40 mAb.
Conclusions:
- Conditional CD40 activation via α-FAPxCD40, restricted by FAP expression, enables potent tumor eradication without peripheral toxicity.
- This targeted approach suggests a potentially improved therapeutic index for CD40-based cancer immunotherapy.
- α-FAPxCD40 shows promise for treating solid tumors and is currently under investigation in a first-in-human clinical trial.
