Posted June 23, 2023

Kyoji Tsuchikama, Ph.D., UTHealth Houston

Intratumor heterogeneity of human epidermal growth factor receptor 2 (HER2) expression presents an important challenge for the treatment of breast cancer and is associated with high relapse rates due to acquired treatment resistance, aggressive growth, and poor survival. Antibodies coupled with a payload (cytotoxic agent), known as antibody–drug conjugates (ADCs), have been shown to provide targeted therapy delivery to HER2-positive breast cancer tumors for increased efficacy and decreased adverse effects. However, intratumor HER2 heterogeneity limits the efficacy of ADCs. Recently, the concept of co-delivery of two separate payloads from a single antibody (dual-drug ADC) has been suggested as a potential method to overcome this challenge. With support from a fiscal year 2017 Breast Cancer Research Program Breakthrough Award – Funding Level 2, Dr. Kyoji Tsuchikama designed and evaluated the HER2-targeted killing potency, pharmacokinetic profile, and toxicity of single- and dual-drug ADCs in cell lines and mouse models of breast cancer.

Dr. Tsuchikama and his team reported in Nature Communications their production of both single-drug ADCs, containing payload molecules monomethyl auristatin E or monomethyl auristatin F, and dual-drug ADCs, containing both payloads to kill a wider range of breast cancer cells by combining their different molecular and pharmacological properties. The team created ADCs using a novel glutamic acid–valine–citrulline linker system developed by the team to enable dual-drug assembly as well as ensure in vivo stability. The team constructed several variations of these single- and dual-drug ADCs with differing levels of drug-to-antibody ratios and analyzed their physicochemical properties, efficacy, and toxicity profiles. Characterization of the dual-drug ADCs confirmed that the physicochemical properties and antigen binding are not impaired by their molecular design and conjugation strategy. The researchers observed that the cytotoxic activity of the dual-drug ADCs was high in HER2-expressing cell lines and not significant in the HER2-negative cell lines, demonstrating specificity. The dual-drug ADCs were also potent in breast cancer cell line models of drug resistance, suggesting a potential utility in addressing this significant challenge in the treatment of HER2-positive breast cancer. Similarly, the team showed that the dual-drug ADCs had antitumor activity (diminishing both tumor size and weight) in two mouse models representing intratumor HER2 heterogeneity and elevated drug resistance. Notably, the investigators found that the dual-drug ADCs were more potent than any single-drug ADC and observed only minimal toxicity at therapeutic levels in both in-vitro and in-vivo studies, with dual-drug ADCs having the least toxicity. Finally, co-administration of two single-drug ADCs led to decreased payload delivery efficacy due to competitive binding, demonstrating that a dual-drug ADC may be a more advantageous approach.

Overall, Dr. Tsuchikama’s linker technology improved tumor-targeting specificity and payload delivery efficiency of dual-drug ADCs in breast cancer mouse models. These results demonstrate that the therapeutic potential of their dual-drug ADCs is a step toward overcoming the challenges associated with breast cancer heterogeneity and drug resistance. Further assessment of dual-drug ADC toxicity and safety profiles in preclinical models may pave the way for evaluation of dual-drug ADCs in clinical trials for the treatment of refractory HER2-positive breast cancer.

Publication:
Yamazaki CM, Yamaguchi A, Anami Y, et al. 2021. Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance. Nature Communications 12(1):3528.

Links:
Public and Technical Abstracts: Dual-Loading ADCs for Combating Cancer Drug Resistance and Heterogeneity

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