Immunoconjugates for Osteosarcoma Therapy: Preclinical Experiences and Future Perspectives

Abstract

Osteosarcoma (OS) is an aggressive osteoid-producing tumor of mesenchymal origin, which represents the most common primary bone malignancy. It is characterized by a complex and frequently uncertain etiology. The current standard care for high-grade OS treatment is neoadjuvant chemotherapy, followed by surgery and post-operative chemotherapy. In order to ameliorate survival rates of patients, new therapeutic approaches have been evaluated, mainly immunotherapy with antibody-drug conjugates or immunoconjugates. These molecules consist of a carrier (frequently an antibody) joined by a linker to a toxic moiety (drug, radionuclide, or toxin). Although several clinical trials with immunoconjugates have been conducted, mainly in hematological tumors, their potential as therapeutic agents is relatively under-explored in many types of cancer. In this review, we report the immunoconjugates directed against OS surface antigens, considering the in vitro and in vivo studies. To date, several attempts have been made in preclinical settings, reporting encouraging results and demonstrating the validity of the idea. The clinical experience with glembatumumab vedotin may provide new insights into the real efficacy of antibody-drug conjugates for OS therapy, possibly giving more information about patient selection. Moreover, new opportunities could arise from the ongoing clinical trials in OS patients with unconjugated antibodies that could represent future candidates as carrier moieties of immunoconjugates.

Orai1 Promotes Osteosarcoma Metastasis by Activating the Ras-Rac1-WAVE2 Signaling Pathway

“…Metastasis is an important marker of tumor progression to the final stage. Although metastasis accounts for about 90% of cancer-related mortality, the molecular mechanism of tumor metastasis is still poorly understood [1–4]. Migration, invasion, and adhesion of tumor cells are important steps in the process of tumor metastasis [5–7].…”

“…Osteosarcoma is a highly malignant bone tumor, mainly occurring in children and adolescents. The treatment of osteosarcoma has improved significantly over the past 30 years and multi-drug chemotherapy has improved the 5-year survival rate of patients with osteosarcoma to 60~78%; however, the survival rate of patients with osteosarcoma remains low, with an overall 5-year survival rate of just 11–20% [1–4]. Therefore, it is necessary to find a new method to effectively inhibit the metastasis of osteosarcoma.…”

“…Osteosarcoma is a highly malignant bone cancer that mainly occurs in children and adolescents. Currently, the survival rate of patients with metastatic osteosarcoma is very low, with an overall 5-year survival rate of just 11–20% [1–4]. Therefore, it is necessary to find an effective method to inhibit the metastasis of osteosarcoma.…”

Flavonoid compound breviscapine suppresses human osteosarcoma Saos‐2 progression property and induces apoptosis by regulating mitochondria‐dependent pathway

“…Although there are many modern therapies, including chemotherapy, radiotherapy, and comprehensive surgery, which are commonly used in clinical practice, the morbidity and mortality of patients with OS are still high. [25,26] Conventional chemoradiotherapy is likely to cause serious side effects, often leading to drug resistance. In addition, due to the rapid growth of OS in the early stage, it easily infiltrates and metastasizes to other tissues, and there is still a large recurrence probability after surgical resection.…”

Synthesis of a tubugi-1-toxin conjugate by a modulizable disulfide linker system with a neuropeptide Y analogue showing selectivity for hY1R-overexpressing tumor cells

“…Such targeted therapeutics are able to address transformed cells selectively by recognition of disease-associated membrane structures, e.g., dysregulated membrane proteins, or by modulation of metabolic or regulatory characteristics that are specific or at least differential for tumor cells. Members of one prominent novel class of targeted anticancer drugs that has been developed over the last years are antibody–drug conjugates (ADCs) [9–11]. Due to their high antibody-mediated target specificity, ADCs are designed for selective treatments of tumor cells with very potent, mostly cytotoxic drug molecules while avoiding or at least limiting the off-target toxicity that would be characteristic for the stand-alone cytotoxic drugs.…”