scholarly journals Harnessing the power of antibodies to fight bone metastasis

2021 ◽  
Vol 7 (26) ◽  
pp. eabf2051
Author(s):  
Zeru Tian ◽  
Ling Wu ◽  
Chenfei Yu ◽  
Yuda Chen ◽  
Zhan Xu ◽  
...  
Keyword(s):  
Clinical Success ◽  
Bone Diseases ◽  
Bone Lesions ◽  
Therapeutic Antibodies ◽  
Bone Microenvironment ◽  
Bone Targeting ◽  
Promising Strategy ◽  
Physical Barriers ◽  
Antibody Conjugation ◽  
Xenograft Mice

Antibody-based therapies have proved to be of great value in cancer treatment. Despite the clinical success of these biopharmaceuticals, reaching targets in the bone microenvironment has proved to be difficult due to the relatively low vascularization of bone tissue and the presence of physical barriers. Here, we have used an innovative bone-targeting (BonTarg) technology to generate a first-in-class bone-targeting antibody. Our strategy involves the use of pClick antibody conjugation technology to chemically couple the bone-targeting moiety bisphosphonate to therapeutic antibodies. Bisphosphonate modification of these antibodies results in the delivery of higher conjugate concentrations to the bone metastatic niche, relative to other tissues. In xenograft mice models, this strategy provides enhanced inhibition of bone metastases and multiorgan secondary metastases that arise from bone lesions. Specific delivery of therapeutic antibodies to the bone, therefore, represents a promising strategy for the treatment of bone metastatic cancers and other bone diseases.

Harnessing the Power of Antibodies to Fight Bone Metastasis

2021 ◽  
Author(s):  
Zeru Tian ◽  
Ling Wu ◽  
Chenfei Yu ◽  
Yuda Chen ◽  
Zhan Xu ◽  
...  
Keyword(s):  
Bone Metastases ◽  
Clinical Success ◽  
Growth Factor Receptor ◽  
Bone Diseases ◽  
Bone Lesions ◽  
Therapeutic Antibodies ◽  
Her2 Positive ◽  
Bone Targeting ◽  
Physical Barriers ◽  
Antibody Conjugation

AbstractOver the past 20 years, antibody-based therapies have proved to be of great value in cancer treatment. Despite the clinical success of these biopharmaceuticals, reaching targets in the bone micro-environment has proved to be difficult perhaps due to the relatively low vascularization of bone tissue and the presence of physical barriers that impair drug penetration. Here, we have used an innovative bone targeting (BonTarg) technology to generate a first-in-class bone-targeting anti-body. Moreover, we have used two xenograft models to demonstrate the enhanced therapeutic efficacy of this bone-targeting antibody against bone metastases, compared to the efficacy of traditional antibodies. Our strategy involves the use of pClick antibody conjugation technology to chemically couple the bone-targeting moiety bisphosphonate to the human epidermal growth factor receptor 2 (HER2)-specific antibody trastuzumab. Bisphosphonate modification of therapeutic antibodies results in delivery of higher conjugate concentrations to the bone metastatic niche, relative to other tissues. In both HER2-positive and negative xenograft mice models, this strategy provides enhanced inhibition of experimental bone metastases as well as multi-organ secondary metastases that arise from the bone lesions. Specific delivery of therapeutic antibodies to the bone therefore represents a promising strategy for the treatment of bone metastatic cancers and other bone diseases.

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

2021 ◽  
Author(s):  
Zeru Tian ◽  
Chenfei Yu ◽  
Weijie Zhang ◽  
Kuan-lin Wu ◽  
Ruchi Gupta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastases ◽  
Bone Tumor ◽  
Cancer Metastasis ◽  
Antibody Therapy ◽  
Breast Cancer Metastasis ◽  
Bone Lesions ◽  
Therapeutic Antibodies ◽  
Bone Targeting ◽  
Homing Peptide

Therapeutic antibodies have gone a long way toward realizing their clinical potential and have become very useful for treating a variety of pathologies. Despite the rapid evolution of therapeutic antibodies, their clinical efficacy in treatment of bone tumors has been hampered by the inadequate pharmacokinetics and poor bone tissue accessibility of these large macromolecules. Here, we show that engineering therapeutic antibodies to include bone-homing peptide sequences dramatically enhances their concentration 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 a bone-homing peptide into permissive internal sites of the anti-HER2 antibody trastuzumab. Compared to the unmodified antibody, the engineered bone-targeting antibodies have similar pharmacokinetics and in vitro cytotoxic activity against HER2-positive cancer cells, 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 multi-organ metastases from bone lesions. 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 delivery of therapeutic antibodies to the bone tumor niche. This provides a powerful strategy for overcoming inadequate treatment of bone cancer and the development of potentially acquired resistance to therapy.

scholarly journals Targeting regulatory T cells for immunotherapy in melanoma

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Lili Huang ◽  
Yeye Guo ◽  
Shujing Liu ◽  
Huaishan Wang ◽  
Jinjin Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Immune Cells ◽  
Therapeutic Efficacy ◽  
Patient Survival ◽  
Therapeutic Antibodies ◽  
Promising Strategy ◽  
Fine Tune

AbstractRegulatory T cells (Tregs) are essential in the maintenance of immunity, and they are also a key to immune suppressive microenvironment in solid tumors. Many studies have revealed the biology of Tregs in various human pathologies. Here we review recent understandings of the immunophenotypes and suppressive functions of Tregs in melanoma, including Treg recruitment and expansion in a tumor. Tregs are frequently accumulated in melanoma and the ratio of CD8+ T cells versus Tregs in the melanoma is predictive for patient survival. Hence, depletion of Tregs is a promising strategy for the enhancement of anti-melanoma immunity. Many recent studies are aimed to target Tregs in melanoma. Distinguishing Tregs from other immune cells and understanding the function of different subsets of Tregs may contribute to better therapeutic efficacy. Depletion of functional Tregs from the tumor microenvironment has been tested to induce clinically relevant immune responses against melanomas. However, the lack of Treg specific therapeutic antibodies or Treg specific depleting strategies is a big hurdle that is yet to be overcome. Additional studies to fine-tune currently available therapies and more agents that specifically and selectively target tumor infiltrating Tregs in melanoma are urgently needed.

A Novel Anilinoquinazoline Derivative Inhibits Growth of High-Risk Myeloma Cells In Vivo and Regulates Differentiation of Osteoclasts

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4076-4076
Author(s):  
Yoshie Ozaki ◽  
Yuhei Naito ◽  
Hiroshi Yanagawa ◽  
Yuya Suzuki ◽  
Wenlin Du ◽  
...  
Keyword(s):  
High Risk ◽  
Cell Lines ◽  
High Performance ◽  
Mononuclear Cells ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Bone Diseases ◽  
Bone Lesions ◽  
Tartrate Resistant Acid Phosphatase

Abstract Abstract 4076 Purpose: Despite recent advances in the use of newly developed drugs, high-risk multiple myeloma (MM) patients harboring del13q, t(4;14) or del17p revealed significantly shorter survival. To overcome the limitation, we have screened forty synthetic anilinoquinazoline (AQ) derivatives, and found a novel compound, Q15, which significantly inhibited the growth of MM cell lines with high-risk chromosomal abnormalities. The purpose of this study is to examine anti-tumor and anti-osteoclastogenic activities of Q15 and to clarify the possibility of development of new drug effective for high-risk MM and bone diseases. Methods and Results: Forty AQ derivatives were synthesized and screened for anti-proliferative effect on KMS34 cells. Q15 strongly inhibited growth of t(4;14)-positive KMS34 cells and induced apoptosis in much lower concentration (IC50=78nM) compared with gefitinib (IC50=2500nM), a representative AQ. Q15 also inhibited growth of other MM cell lines harboring high-risk chromosomal abnormalities. It was also found that Q15 did not inhibit intracellular tyrosine phosphorylation induced by EGF, FGF-2, HGF and IL-6, suggesting that Q15 showed anti-tumor activity in a different mechanism from that of gefitinib. In vivo anti-myeloma activity was evaluated by intraperitoneal injection of Q15 into KMS34-bearing lcr/SCID mice. Twenty mg/kg Q15 significantly delayed the tumor growth in these mice. Histopathological examinations revealed apoptosis of MM cells in Q15-treated mice. Growth of colony-forming cells was not suppressed by much higher concentrations (25μ M) of Q15 than IC50, suggesting low hematopoietic toxicity of Q15. In pharmacokinetic study using high-performance liquid chromatography (HPLC), the plasma concentration of Q15 in mice reached a maximum (Cmax=4.5μ M) at 1.5hr after injection, and its half life (T1/2) was 4.5hr. In addition, anti-osteoclastogenic activity was also examined by adding Q15 to M-CSF/RANK ligand-induced osteoclastogenic culture of bone marrow mononuclear cells from C57BL/6JJcl mice. The number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts was reduced in the presence of Q15. Conclusion: Q15, a novel AQ derivative, has anti-MM activity in vivo and is a potentially safe and effective drug for high-risk MM with bone lesions. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Management of Myeloma Bone Lesions

2021 ◽  
Vol 22 (7) ◽  
pp. 3389
Author(s):  
Jeng-Shiun Du ◽  
Chia-Hung Yen ◽  
Chin-Mu Hsu ◽  
Hui-Hua Hsiao
Keyword(s):  
Bone Disease ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Bone Destruction ◽  
Cord Compression ◽  
Bone Diseases ◽  
Novel Agents ◽  
Bone Lesions ◽  
Skeletal Involvement ◽  
Skeletal Related Events

Multiple myeloma (MM) is a B-cell neoplasm characterized by clonal plasma–cell proliferation. The survival and prognosis of this condition have been significantly improved by treatment with active anti-MM drugs such as bortezomib or lenalidomide. Further, the discovery of novel agents has recently paved the way for new areas of investigation. However, MM, including myeloma-related bone diseases, remains fatal. Bone disease or bone destruction in MM is a consequence of skeletal involvement with bone pain, spinal cord compression, and bone fracture resulting from osteolytic lesions. These consequences affect disease outcomes, including patients’ quality of life and survival. Several studies have sought to better understand MM bone disease (MBD) through the classification of its molecular mechanisms, including osteoclast activation and osteoblast inhibition. Bisphosphonates and the receptor activator of the nuclear factor-kappa B (NF-κB) ligand (RANKL) inhibitor, denosumab, prevent skeletal-related events in MM. In addition, several other bone-targeting agents, including bone-anabolic drugs, are currently used in preclinical and early clinical evaluations. This review summarizes the current knowledge of the pathogenesis of MBD and discusses novel agents that appear very promising and will soon enter clinical development.

scholarly journals Role of high resolution computed tomography in the evaluation of temporal bone lesions: our experience

2016 ◽  
Vol 2 (3) ◽  
pp. 135
Author(s):  
Jyothi A. C. ◽  
Shrikrishna B. H.
Keyword(s):  
Computed Tomography ◽  
High Resolution ◽  
Temporal Bone ◽  
Visual Information ◽  
Bone Neoplasms ◽  
Bone Diseases ◽  
Bone Lesions ◽  
High Resolution Computed Tomography ◽  
Imaging Tool ◽  
Structural Details

<p class="abstract"><strong>Background:</strong> High resolution computed tomography (HRCT) is a modification of routine computed tomography. It provides visual information of the minute structural details of the temporal bone. The present study aimed at studying the pathological processes of the temporal bone and their extent using HRCT.</p><p class="abstract"><strong>Methods:</strong> This prospective study was done by taking HRCT of the temporal bone in 50 patients who presented to us with clinical features of temporal bone diseases. Both contrast and no enhanced images were obtained by taking 2mm sections using ultra high algorithm in both coronal and axial planes. The results were then analysed statistically.  </p><p class="abstract"><strong>Results:</strong> Amongst the 50 cases, infection was the most common pathology affecting the temporal bone.  Neoplasms formed the second largest group of lesions with acoustic neuroma being the most common tumour.</p><p><strong>Conclusions:</strong> HRCT is a revolutionary imaging tool in evaluating the various pathologies affecting the temporal bone. It identifies the hidden areas of the temporal bone. It also lays down an anatomical roadmap for the surgeon preoperatively. </p>

Preliminary Study for Co-Culture of Osteoblasts and Endothelial Cells to Construct the Regenerative Bone

2017 ◽  
Vol 758 ◽  
pp. 269-272 ◽  
Author(s):  
Michiyo Honda ◽  
Mamoru Aizawa
Keyword(s):  
Tissue Engineering ◽  
Endothelial Cells ◽  
Bone Development ◽  
Three Dimensional ◽  
Bone Defects ◽  
Culture Conditions ◽  
Bone Diseases ◽  
Promising Strategy ◽  
Novel Treatment ◽  
Preliminary Study

Vascularization is a crucial process during bone development and regeneration. A number of studies have shown that the interaction between osteoblasts and endothelial cells plays a key role in osteogenesis by using co-culture system. However, vascularization strategies in cell-based bone tissue engineering depend on optimal culture conditions. In this study, we determined the optimal co-culture conditions in view of osteogenic parameters and examined the effects of angiogenic properties on osteogenesis. As for cell proliferation, the proportion of osteoblasts increased and that of endothelial cells decreased as culture period passed. Assessment of osteogenic differentiation shows that co-culture of osteoblasts and endothelial cells significantly increased alkaline phosphatase activity and expression of bone-related genes. Furthermore, abundant microcapillary-like structures were observed which endothelial cells self-assembled into branches and net-like structures. The use of endothelial cells would be a promising strategy to promote vascularization to support the bone regeneration. Combination of these cell-based approaches and tissue engineering like three-dimensional scaffolds could provide a novel treatment therapy for bone defects and bone diseases.

Bone Microenvironment Cells Show a Different Pattern of Gene Expression Profiling in Relationship with the Presence of Osteolytic Bone Lesions in Multiple Myeloma Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2740-2740
Author(s):  
Katia Todoerti ◽  
Gina Lisignoli ◽  
Simona Colla ◽  
Paola Storti ◽  
Luca Agnelli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Differentially Expressed ◽  
Bone Lesions ◽  
Bone Microenvironment ◽  
Bone Status ◽  
Transcriptional Alterations ◽  
Cellular Types

Abstract Multiple myeloma (MM) is a plasma cell malignancy with the high capacity to induce osteolytic bone lesions. Whereas previous studies identified genes overexpressed by MM cells related to the bone status, the occurrence of transcriptional alterations in the bone microenvironment cells in the relationship with the bone involvement has not yet investigated. To clarify this issue, in this study we have analyzed the gene expression profiling of mesenchymal (MSC) and osteoblastic (OB) cells obtained from MM patients (n=24; osteolytic n=10; non-osteolytic n=14) in relationship with the presence or absence of osteolytic bone lesions. MGUS subjects (n=7) and healthy donors (n=8) were also included in the study as controls. Both MSC and OB were isolated from trabecular bone biopsies without in vitro differentiation. The presence of potential contaminating cells was excluded by FACS analysis in both MCS and OB, testing CD3, CD14, CD20 and CD138 antigens, as well as the expression of CD105 and CD146; the osteoblast-related markers Osteocalcin, Alkaline Phosphatase, Collagen I and Runx2 were evaluated in OB in comparison with MSC. Thereafter a gene expression profiling analysis of isolated MSC and OB cells was performed using GeneChip® HG-U133A oligonucleotide arrays. The obtained data were validated by real time PCR. Using conventional hierarchical clustering, the unsupervised analyses performed of the whole dataset generated a dendrogram clearly distinguishing MSC and OB cellular types. When considering MSC and OB dataset separately, a preferential clustering in relation to the presence of osteolytic bone lesions was observed for MSC but not OB samples. A supervised multi class analysis identified a total of 84 probe sets differentially expressed in MSC with an intermediate transcriptional profile in MGUS-MSC between osteolytic and non osteolytic MM patients. A supervised analysis performed on MSC MM samples revealed a total of 49 probe-sets (36 up-regulated and 9 down-regulated genes) as differentially expressed in osteolytic vs. non-osteolytic patients. Specifically, genes belonging to Wnt signaling as WNT6 and extracellular matrix structure as decorin (DCN) were found to be down-regulated in osteolytic as compared to and non-osteolytic MSC. Interestingly, no significantly modulated genes were found by comparing osteolytic and non-osteolytic OB samples. Finally, we performed two distinct supervised analyses by comparing the two cellular types (MSC and OB) in the two groups of MM patients in relationship with the bone status. A distinct transcriptional pattern was observed in MSC versus OB between osteolytic and non-osteolytic MM patients (52 vs. 21 differentially expressed probe-sets, respectively), mainly involving cell-cycle realted genes. Our results highlight that in MM bone microenvironment MSC rather than OB show transcriptional alterations in relationship with the presence of osteolytic bone lesions in MM patients.

Bone Spared Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-6-SCI-6
Author(s):  
Gregory R. Mundy
Keyword(s):  
Natural History ◽  
Conflicts Of Interest ◽  
Bone Destruction ◽  
Host Cells ◽  
Bone Lesions ◽  
Neoplastic Disease ◽  
Bone Microenvironment ◽  
Preclinical Models ◽  
Myeloma Cells ◽  
History Of

Abstract Abstract SCI-6 After many years, the precise role of the bone microenvironment in the initiation and progression of myeloma is still quite poorly understood. In part, this may be because it has such a complex but important role in the natural history of myeloma. Myeloma cells have dramatic effects on bone, which are well known. These effects are mediated by the effects of myeloma cells on the cells responsible for the normal bone remodeling cycle. What is less well appreciated is the effects of bone and its cellular constituents on the myeloma cells. It is apparent that myeloma cells interact closely with osteoclasts, osteoblasts and also marrow stromal cells in the bone microenvironment and these interactions probably lead to a change in the phenotype of the myeloma cells, and the subsequent production of factors that are associated with the bone destruction which is so common in myeloma. It is also becoming more appreciated that the actual quality of bone and its rigidity and integrity may have important effects on the myeloma cells. The bone loss associated with myeloma and the interaction of myeloma cells with host cells in the bone microenvironment seem to be local effects rather than generalized effects. The bone manifestations of myeloma, even at the clinical level, are still not well understood. For example, it is extremely likely that generalized osteoporosis is far more common in myeloma than is appreciated and occurs even in the presence of lytic bone lesions, and that bone mass may continue to decline in patients in remission. In experimental preclinical models of myeloma, it is quite apparent that modulation of the bone microenvironment has quite dramatic effects on the behavior of the myeloma cells and so the notion if the bone disease of myeloma could be abrogated or removed, the natural history of the neoplastic disease may be very different. Experiments are underway in the preclinical models to investigate this intriguing possibility. Disclosures No relevant conflicts of interest to declare.

scholarly journals Antibody Conjugates-Recent Advances and Future Innovations

Antibodies ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 2 ◽  
Author(s):  
Donmienne Leung ◽  
Jacqueline M. Wurst ◽  
Tao Liu ◽  
Ruben M. Martinez ◽  
Amita Datta-Mannan ◽  
...  
Keyword(s):  
Drug Targets ◽  
Clinical Success ◽  
Lessons Learned ◽  
Magic Bullet ◽  
Success Rates ◽  
Cell Surface Antigens ◽  
Antibody Conjugates ◽  
Antibody Discovery ◽  
Antibody Conjugation ◽  
Made In

Monoclonal antibodies have evolved from research tools to powerful therapeutics in the past 30 years. Clinical success rates of antibodies have exceeded expectations, resulting in heavy investment in biologics discovery and development in addition to traditional small molecules across the industry. However, protein therapeutics cannot drug targets intracellularly and are limited to soluble and cell-surface antigens. Tremendous strides have been made in antibody discovery, protein engineering, formulation, and delivery devices. These advances continue to push the boundaries of biologics to enable antibody conjugates to take advantage of the target specificity and long half-life from an antibody, while delivering highly potent small molecule drugs. While the “magic bullet” concept produced the first wave of antibody conjugates, these entities were met with limited clinical success. This review summarizes the advances and challenges in the field to date with emphasis on antibody conjugation, linker-payload chemistry, novel payload classes, absorption, distribution, metabolism, and excretion (ADME), and product developability. We discuss lessons learned in the development of oncology antibody conjugates and look towards future innovations enabling other therapeutic indications.

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