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Updated: Jul 16, 2026
Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
Targeted antibody-drug conjugates for rhabdomyosarcoma and other FGFR4-expressing cancers
Meijie Tian1, Katrina Jia1, Jerry T Wu1
1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Abstract:
Compared with chimeric antigen receptor (CAR) T cell therapy, antibody-drug conjugates (ADCs) offer distinct advantages. Here, we report on two FGFR4-targeted ADCs, using the high-affinity monoclonal antibody 3A11, the same binder used in a CAR T cell format that is being evaluated at the NCI (NCT06865664) for patients with relapsed/refractory rhabdomyosarcoma (RMS). These ADCs, conjugated to monomethyl auristatin E (MMAE) or an exatecan derivative, are rapidly internalized, causing potent fibroblast growth factor receptor 4 (FGFR4)-dependent cytotoxicity in vitro. In subcutaneous RMS xenograft models, both ADCs demonstrated robust anti-tumor activities, significantly prolonging survival. Notably, exatecan-ADC showed better efficacy, with durable tumor control, in aggressive fusion-negative (FN) RMS559 and fusion-positive (FP) RH4 RMS cell-line-derived xenografts (CDXs) and a patient-derived RMS xenograft (PDX). Furthermore, exatecan-ADC effectively controls tumors in an FGFR4-expressing MDA-MB-453 breast cancer mouse model, eradicating relapsed tumors with retreatment. These findings highlight FGFR4-targeted ADCs as potent therapeutic agents against aggressive FGFR4-expressing malignancies, supporting their further clinical development.
Insights
Antibody-drug conjugates targeting fibroblast growth factor receptor 4 (FGFR4) show potent anti-tumor activity. These FGFR4-targeted ADCs demonstrate efficacy in preclinical models of rhabdomyosarcoma and breast cancer.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Antibody-drug conjugates (ADCs) present advantages over chimeric antigen receptor (CAR) T cell therapy.
- Fibroblast growth factor receptor 4 (FGFR4) is a target in certain aggressive malignancies.
Purpose of the Study:
- To evaluate the efficacy of two novel FGFR4-targeted ADCs in preclinical models.
- To compare the therapeutic potential of ADCs conjugated with different payloads.
Main Methods:
- Development of two ADCs utilizing the 3A11 antibody targeting FGFR4, conjugated to MMAE or an exatecan derivative.
- In vitro assessment of cytotoxicity and internalization.
- In vivo evaluation in rhabdomyosarcoma (RMS) xenograft models (CDX and PDX) and an FGFR4-expressing breast cancer model.
Main Results:
- Both ADCs exhibited potent FGFR4-dependent cytotoxicity in vitro.
- ADCs demonstrated significant anti-tumor activity and prolonged survival in RMS xenograft models.
- The exatecan-ADC showed superior efficacy and durable tumor control in aggressive RMS and breast cancer models, including with retreatment.
Conclusions:
- FGFR4-targeted ADCs are effective therapeutic agents against aggressive FGFR4-expressing cancers.
- The exatecan-ADC exhibits promising preclinical efficacy, supporting further clinical development.
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