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Updated: Aug 10, 2025
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Comparison of HER2-targeted affibody conjugates loaded with auristatin- and maytansine-derived drugs
Wen Yin1, Tianqi Xu2, Haozhong Ding1
1Department of Protein Science, KTH Royal Institute of Technology, Roslagstullsbacken 21, 114 17 Stockholm, Sweden.
Abstract:
Treatment with antibody drug conjugates targeting receptors over-expressed on cancer cells is well established for clinical use in several types of cancer, however, resistance often occurs motivating the development of novel drugs. We have recently investigated a drug conjugate consisting of an affibody molecule targeting the human epidermal growth factor receptor 2 (HER2), fused to an albumin-binding domain (ABD) for half-life extension, loaded with the cytotoxic maytansine derivative DM1. In this study, we investigated the impact of the cytotoxic payload on binding properties, cytotoxicity and biodistribution by comparing DM1 with the auristatins MMAE and MMAF, as part of the drug conjugate. All constructs had specific and high affinity binding to HER2, human and mouse albumins with values in the low- to sub-nM range. ZHER2-ABD-mcMMAF demonstrated the most potent cytotoxic effect on several HER2-over-expressing cell lines. In an experimental therapy study, the MMAF-based conjugate provided complete tumor regression in 50% of BALB/c nu/nu mice bearing HER2-over-expressing SKOV3 tumors at a 2.9 mg/kg dose, while the same dose of ZHER2-ABD-mcDM1 provided only a moderate anti-tumor effect. A comparison with the non-targeting ZTaq-ABD-mcMMAF control demonstrated HER2-targeting specificity. In conclusion, a combination of potent cytotoxicity in vitro, with minimal uptake in normal organs in vivo, and efficient delivery to tumors provided a superior anti-tumor effect of ZHER2-ABD-mcMMAF, while maintaining a favorable toxicity profile with no observed adverse effects.
Insights
This study compares different cytotoxic payloads for HER2-targeted antibody drug conjugates. The MMAF-based conjugate showed superior tumor regression and a favorable safety profile compared to DM1.
Area of Science:
- Oncology
- Pharmacology
- Bioconjugation
Background:
- Antibody drug conjugates (ADCs) targeting over-expressed receptors are established cancer therapies.
- Resistance to existing ADCs necessitates the development of novel therapeutic agents.
- The study focuses on affibody-based ADCs targeting human epidermal growth factor receptor 2 (HER2).
Purpose of the Study:
- To investigate the impact of different cytotoxic payloads (DM1, MMAE, MMAF) on HER2-targeted affibody conjugates.
- To compare binding properties, in vitro cytotoxicity, and in vivo biodistribution of these novel drug conjugates.
- To evaluate the anti-tumor efficacy and toxicity profile of the most promising conjugate.
Main Methods:
- Construction of affibody-based drug conjugates incorporating an albumin-binding domain (ABD) for extended half-life.
- Assessment of binding affinity to HER2 and albumins (human and mouse).
- Evaluation of in vitro cytotoxicity against HER2-over-expressing cell lines.
- In vivo efficacy studies in mice bearing HER2-positive tumors and biodistribution analysis.
Main Results:
- All conjugates exhibited high affinity binding to HER2 and albumins.
- ZHER2-ABD-mcMMAF demonstrated the most potent in vitro cytotoxicity.
- The MMAF-based conjugate achieved complete tumor regression in 50% of treated mice at a low dose.
- DM1-based conjugate showed only moderate anti-tumor effects.
- HER2-targeting specificity was confirmed using a non-targeting control conjugate.
- Minimal uptake in normal organs was observed for the MMAF-based conjugate.
Conclusions:
- The MMAF-based affibody conjugate (ZHER2-ABD-mcMMAF) exhibits superior anti-tumor efficacy compared to the DM1-based conjugate.
- This improved efficacy is attributed to potent cytotoxicity, efficient tumor delivery, and minimal off-target uptake.
- The ZHER2-ABD-mcMMAF conjugate presents a promising therapeutic candidate with a favorable toxicity profile for HER2-expressing cancers.
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