Harnessing the power of antibodies to fight bone metastasis

Tian, Zeru; Wu, Ling; Yu, Chenfei; Chen, Yuda; Xu, Zhan; Bado, Igor; Loredo, Axel; Wang, Hai; Wu, Kuan‐Lin; Zhang, Weijie; Zhang, Xiang H.-F.; Xiao, Han

doi:10.1126/sciadv.abf2051

Cited by 21 publications

(13 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 40 , 46 The resulting bone-targeting antibody was demonstrated to be effective in treating breast cancer bone metastasis in preclinical models. 46 Alendronate has a strong affinity for calcium phosphate surfaces. However, it is important to test the antitumor activities of antibodies with various bone-targeting abilities, as excessive affinity to bones may lead to reduced accessibility to entire metastatic lesions.…”

Section: Discussionmentioning

confidence: 99%

“…Antibody-based trastuzumab (Herceptin) and pertuzumab (Perjeta) therapies are established as the standard of care for HER2+ adjuvant and metastatic breast cancer. , Although many HER2+ bone metastatic breast cancer patients benefit from these treatments, few experience prolonged remission. ,− Of patients with HER2-positive bone metastases, only 17% achieved a complete response and none achieved a durable complete response. By comparison, 40% and 30% of patients with liver metastases achieved complete responses and durable complete responses, respectively.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Tian

Zhang

et al. 2022

ACS Cent. Sci.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Tian

Zhang

et al. 2022

ACS Cent. Sci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…This chemically synthesized FB peptide was applied to the synthesis of ADCs and bispecific small molecule–antibody conjugates with both excellent in vitro cytotoxic activity and antitumor activity in mouse xenograft models . Furthermore, this strategy was recently employed to prepare the first bone-targeting antibody, which is able to enhance the biodistribution to the bone and dramatically increase the therapeutic effect to HER2+ breast cancer bone metastasis in murine models . In 2019, Ito’s group reported a similar lysine modification approach (CCAP) using N -hydroxysuccinimide ester as a proximity-based reactive probe (Figure B) .…”

Section: Proximity-based Modificationmentioning

confidence: 99%

“…99 Furthermore, this strategy was recently employed to prepare the first bonetargeting antibody, which is able to enhance the biodistribution to the bone and dramatically increase the therapeutic effect to HER2+ breast cancer bone metastasis in murine models. 100 In 2019, Ito's group reported a similar lysine modification approach (CCAP) using N-hydroxysuccinimide ester as a proximity-based reactive probe (Figure 5B). 101 By precise control of the pH and reactant concentrations, Fc-III peptide modified with an NHS-ester linker could conjugate to antibodies with a high efficiency.…”

Section: ■ Proximity-based Modificationmentioning

confidence: 99%

Precision Modification of Native Antibodies

Lee

et al. 2021

Bioconjugate Chem.

Self Cite

View full text Add to dashboard Cite

Antibodies, particularly of the immunoglobulin G (IgG) isotype, are a group of biomolecules that are extensively used as affinity reagents for many applications in research, disease diagnostics, and therapy. Most of these applications require antibodies to be modified with specific functional moieties, including fluorophores, drugs, and proteins. Thus, a variety of methodologies have been developed for the covalent labeling of antibodies. The most common methods stably attach functional molecules to lysine or cysteine residues, which unavoidably results in heterogeneous products that cannot be further purified. In an effort to prepare homogeneous antibody conjugates, bioorthogonal handles have been site-specifically introduced via enzymatic treatment, genetic code expansion, or genetically encoded tagging, followed by functionalization using bioorthogonal conjugation reactions. The resulting homogeneous products have proven superior to their heterogeneous counterparts for both in vitro and in vivo usage. Nevertheless, additional chemical treatment or protein engineering of antibodies is required for incorporation of the bioorthogonal handles, processes that often affect antibody folding, stability, and/or production yield and cost. Accordingly, concurrent with advances in the fields of bioorthogonal chemistry and protein engineering, there is growing interest in site-specifically labeling native (nonengineered) antibodies without chemical or enzymatic treatments. In this review, we highlight recent strategies for producing site-specific native antibody conjugates and provide a comprehensive summary of the merits and disadvantages of these strategies.

show abstract

“…[2][3][4][5] These latent bioreactive Uaas react with natural amino acid residues through proximityenabled reactivity, generating covalent linkages within or between proteins specifically, which have been harnessed to enhance protein properties, to probe protein interactions, and to develop covalent protein drugs. [6][7][8][9][10][11] The most challenging aspect of developing a latent bioreactive Uaa is to finely balance its biocompatibility and reactivity. 12 The Uaa should not react with any biomolecules inside cells to avoid off-target reactions and cytotoxicity, while reacting with the target residue efficiently under mild cellular conditions.…”

mentioning

confidence: 99%