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Updated: Jun 4, 2025
Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
Development and evaluation of a single domain antibody targeting folate receptor alpha for radioligand therapy
Jonatan Dewulf1, Sam Massa1, Laurent Navarro1
1Precirix, Burg. Etienne Demunterlaan 3, Brussels, Matthias, B-1090, Belgium.
Background:
Folate receptor alpha (FRα) overexpression is seen in many cancers. Radioligand therapy (RLT) has emerged as a promising tool to target FRα and has been investigated previously, but further progression was limited due to high kidney retention and, subsequently, toxicity. To circumvent this, we present here the development of a [131I]I-GMIB-conjugated anti-human FRα (hFRα) single-domain antibody (sdAb), with intrinsically fast renal clearance and concomitant low kidney retention. We report the hit-to-lead development of an anti-hFRα sdAb. We evaluated its potential in vitro and assessed its targeting ability using SPECT imaging in hFRα-knockin and tumour-bearing mice. The toxicity and therapeutic efficacy of the [131I]I-GMIB-sdAb were investigated in mouse models.
Results:
The lead anti-hFRα sdAb 2BD42 was developed with picomolar affinities, low koff, and radiolabelled using [131I]I with yields of > 41% and purity > 99%. [131I]I-GMIB-2BD42 retained tumour uptake (> 5%IA/g at 1 h p.i. and > 1.5%IA/g at 24 h p.i.) and fast kidney clearance (< 1%IA/g at 24 h p.i.) in athymic and hFRα-knock-in mice. Athymic mice bearing hFRα-positive xenografts treated with [131I]I-GMIB-2BD42 showed prolonged survival without toxicity compared to animals that received the vehicle solution or radioactive control.
Conclusion:
The therapeutic lead radiopharmaceutical [131I]I-GMIB-2BD42 showed fast pharmacokinetics with specific retention in hFRα + tumours. In addition, we report therapeutic efficacy with no signs of toxicity. In this study, we successfully designed a new drug for RLT, overcoming previous limitations, such as high kidney retention, which could aid in revitalising FRα-targeted radiotherapy.
Insights
A novel radioligand therapy targeting folate receptor alpha (FRα) shows promising results. This new treatment effectively targets FRα-positive tumors with fast clearance and low kidney retention, offering a safer alternative for cancer therapy.
Area of Science:
- Oncology
- Radiochemistry
- Immunotherapy
Background:
- Folate receptor alpha (FRα) is overexpressed in many cancers, making it a target for cancer therapy.
- Previous radioligand therapies (RLT) targeting FRα were limited by high kidney retention and toxicity.
- Developing targeted therapies with improved safety profiles is crucial for effective cancer treatment.
Purpose of the Study:
- To develop a novel single-domain antibody (sdAb) conjugated with a radioisotope for FRα-targeted RLT.
- To evaluate the in vitro and in vivo properties of the developed radiopharmaceutical, including targeting ability, pharmacokinetics, and toxicity.
- To assess the therapeutic efficacy of the novel RLT in preclinical cancer models.
Main Methods:
- Hit-to-lead development of an anti-human FRα (hFRα) sdAb.
- Radiolabeling of the sdAb with iodine-131 ([131I]I-GMIB).
- In vitro characterization, SPECT imaging in hFRα-knockin and tumor-bearing mice, and toxicity and efficacy studies in mouse models.
Main Results:
- The lead anti-hFRα sdAb (2BD42) demonstrated picomolar affinities and was successfully radiolabeled with [131I]I.
- [131I]I-GMIB-2BD42 showed significant tumor uptake and rapid kidney clearance in preclinical models.
- Treatment with [131I]I-GMIB-2BD42 resulted in prolonged survival in mice with hFRα-positive xenografts, without observable toxicity.
Conclusions:
- The developed [131I]I-GMIB-2BD42 exhibits favorable pharmacokinetics, with specific tumor retention and fast renal clearance.
- This novel radiopharmaceutical demonstrates therapeutic efficacy in preclinical models without toxicity, addressing limitations of previous FRα-targeted RLT.
- The findings suggest that this new drug could revitalize FRα-targeted radiotherapy by overcoming issues like high kidney retention.
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