Generation of a Novel SORT1×HER2 Bispecific Antibody-Drug Conjugate Targeting HER2-Low-Expression Tumor

Area of Science:

• Oncology
• Immunotherapy
• Drug Development

Background:

• Human epidermal growth factor receptor 2 (HER2) is a validated target for antibody-drug conjugates (ADCs), but efficacy is limited in patients with low HER2 expression.
• Existing HER2-targeted ADCs offer benefits for high HER2-expressing tumors, yet require optimization for broader patient populations.
• Sortilin-1 (SORT1) is co-expressed with HER2 in tumors and exhibits rapid internalization, making it a potential synergistic target.

Purpose of the Study:

• To develop and evaluate a bispecific antibody-drug conjugate (bsADC) targeting both HER2 and SORT1 to overcome limitations of HER2-targeted ADCs in low HER2-expressing tumors.
• To assess the binding, internalization, and HER2 degradation capabilities of a novel bispecific antibody (bsSORT1×HER2).
• To determine the in vitro cytotoxicity and in vivo antitumor efficacy of the bsADC (bsSORT1×HER2-DXd) in preclinical models.

Main Methods:

• Development of a bispecific antibody (BsAb) targeting HER2 and SORT1 (bsSORT1×HER2).
• Conjugation of the bsBsAb with the cytotoxic payload DXd to create a bsADC (bsSORT1×HER2-DXd).
• Evaluation of bsADC binding, internalization, HER2 degradation, cytotoxicity in HER2-low-expression tumor cells, and antitumor efficacy in an MDA-MB-231 xenograft mouse model.

Main Results:

• The bsSORT1×HER2 antibody demonstrated strong binding and internalization activity on HER2-low-expression tumor cells.
• The bsADC (bsSORT1×HER2-DXd) exhibited potent cytotoxicity against HER2-low-expression tumor cells.
• Significant antitumor efficacy was observed in the MDA-MB-231 xenograft mice model treated with the bsADC.

Conclusions:

• A bispecific antibody-drug conjugate targeting HER2 and SORT1 (bsSORT1×HER2-DXd) is effective against HER2-low-expression tumors.
• This bsADC strategy offers a promising approach to enhance the efficacy of HER2-targeted ADC therapy for a wider range of patients.
• The development of bsADCs targeting co-expressed tumor antigens represents a significant advancement in cancer treatment.