Nat Commun: Bi-drug antibody-drug conjugate: a weapon against the heterogeneity and resistance of breast cancer

Breast cancer is a heterogeneous disease caused by different cell populations with different gene expression profiles
.

The inter-tumor and intra-tumor heterogeneity of breast cancer is the main factor leading to the recurrence and metastasis of the disease after chemotherapy.

Breast cancer is a heterogeneous disease caused by different cell populations with different gene expression profiles

Previous studies have shown that HER2 (human epidermal growth factor receptor 2) is overexpressed in 14-20% of breast cancer patients
.

In 16-36% of HER2-positive breast cancer patients, intratumoral heterogeneity of HER2 expression was observed

The heterogeneity of HER2 is related to the aggressive growth of tumors, high recurrence rate and poor patient survival rate

In addition, after continuous treatment with trastuzumab, the expression level of HER2 will decrease and lead to resistance to anti-HER2 therapy
.

Therefore, the heterogeneity of HER2 is a huge obstacle to the use of HER2 targeted drugs to achieve truly effective treatment

Antibody-drug conjugates (ADCs) are an emerging chemotherapeutic drug that has achieved amazing clinical success, including the drug T-DM1 for the treatment of HER2-positive breast cancer
.

However, these ADCs are also often plagued by problems related to intratumoral heterogeneity

Molecular design and coupling strategy for the synthesis of dual-drug ADCs

Molecular design and coupling strategy for the synthesis of dual-drug ADCs

In this study, the researchers found that homologous ADCs containing two different payloads are a promising class of drugs to solve this clinical challenge
.

The conjugate shows killing efficacy on HER2 specific cells, ideal pharmacokinetic characteristics, minimal inflammation and marginal toxicity at therapeutic doses

It is worth noting that in a xenograft mouse model that exhibits intratumoral HER2 heterogeneity and increased drug resistance, dual-drug ADCs have greater therapeutic effects and survival benefits than the combined use of two single-drug variants.

Construction and characterization of dual-drug ADC

Construction and characterization of dual-drug ADC

All in all, the results of the study reveal the therapeutic potential of dual-drug ADCs in the treatment of refractory breast cancer and other cancers
.

The results of this study reveal the therapeutic potential of dual-drug ADCs in the treatment of refractory breast cancer and other cancers
.
The results of this study reveal the therapeutic potential of dual-drug ADCs in the treatment of refractory breast cancer and other cancers
.

Original source:

Yamazaki, CM, Yamaguchi, A.
, Anami, Y.
et al.
Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance.
Nat Commun 12, 3528 (10 June 2021).

Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance.

 

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