Bone-Specific Enhancement of Antibody Therapy for Breast Cancer Metastasis to Bone

Abstract

Despite the rapid evolution of therapeutic antibodies, their clinical efficacy in the treatment of bone tumors is hampered due to the inadequate pharmacokinetics and poor bone tissue accessibility of these large macromolecules. Here, we show that engineering therapeutic antibodies with bone-homing peptide sequences dramatically enhances their concentrations in the bone metastatic niche, resulting in significantly reduced survival and progression of breast cancer bone metastases. To enhance the bone tumor-targeting ability of engineered antibodies, we introduced varying numbers of bone-homing peptides into permissive sites of the anti-HER2 antibody, trastuzumab. Compared to the unmodified antibody, the engineered antibodies have similar pharmacokinetics and in vitro cytotoxic activity, but exhibit improved bone tumor distribution in vivo . Accordingly, in xenograft models of breast cancer metastasis to bone sites, engineered antibodies with enhanced bone specificity exhibit increased inhibition of both initial bone metastases and secondary multiorgan metastases. Furthermore, this engineering strategy is also applied to prepare bone-targeting antibody–drug conjugates with enhanced therapeutic efficacy. These results demonstrate that adding bone-specific targeting to antibody therapy results in robust bone tumor delivery efficacy. This provides a powerful strategy to overcome the poor accessibility of antibodies to the bone tumors and the consequential resistance to the therapy.

The covert symphony: cellular and molecular accomplices in breast cancer metastasis

“…Antibody-drug conjugates (ADCs) represent a promising approach exemplified by the DESTINY-Breast03 trial of trastuzumab deruxtecan, which demonstrated substantial improvements in overall patient survival for pre-treated metastatic HER2-+ breast cancer ( Hurvitz et al, 2023 ). Experimentally, antibody-drug conjugate Trastuzumab with a hydroxyapatite-binding bone-homing peptide exhibits enhanced therapeutic efficacy in vivo , selectively delivering the agent to the bone metastatic niche ( Tian et al, 2022 ). Overall, many promising new strategies are in development to improve the treatment of metastatic breast cancer which rely on features specific to the metastatic niche to improve therapeutic delivery and increase sensitivity.…”

ALPPL2‐Binding Peptide Facilitates Targeted mRNA Delivery for Efficient Hepatocellular Carcinoma Gene Therapy

“…[11,12] It also helps to prevent potential side effects after a systemic administration. [13] However, current studies on TSPs have mainly been limited to the targeting and therapeutic functions of the peptides themselves. [14,15] The identification of potential peptide receptors on the cancer cell has seldom been reported.…”