Secreted Gal-3BP is a novel promising target for non-internalizing Antibody–Drug Conjugates

Giansanti, Francesco; Capone, Emily; Ponziani, Sara; Piccolo, Enza; Gentile, Roberta; Lamolinara, Alessia; Campli, Antonella Di; Sallese, Michele; Iacobelli, Valentina; Cimini, Annamaria; Laurenzi, Vincenzo De; Lattanzio, Rossano; Piantelli, Mauro; Ippoliti, Roberto; Sala, Gianluca; Iacobelli, Stéfano

doi:10.1016/j.jconrel.2018.12.018

Cited by 33 publications

(43 citation statements)

References 39 publications

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“…Indeed, no significant therapeutic activity of 1959-sss/DM3 was observed in mice xenotransplanted with hNB cells ( Figure S2D ). In line with this observation, staining of live tumor cells with the humanized 1959 anti-LGALS3BP antibody, produced a characteristic punctate pattern in proximity of the external surface of SKNAS, as previously observed in LGALS3BP + neuroblastoma cells [ 30 ]. In contrast, no staining was detected in hNB cells ( Figure 2 C).…”

Section: Resultssupporting

confidence: 82%

“…We have recently developed a new non-internalizing ADC, called 1959-sss/DM3, which is endowed with a marked therapeutic activity in mouse models of human melanoma. The disulfide-linked payload is released within the reducing tumour microenvironment, therefore a therapeutic effect could be generated without antibody internalization [ 30 ]. We and others have previously ascertained that LGALS3BP is expressed in tumor cells and the extracellular matrix in the majority of neuroblastoma biopsies, but it is not accumulated in adjacent normal tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, engagement of the LGALS3BP receptor galectin 3 mediates IL-6 production from bone marrow mesenchymal stem cells. Accordingly, it has been recently observed that serum levels of LGALS3BP are increased compared to controls in patients with neuroblastoma [ 17 , 23 , 30 , 32 ]. In this study, we confirmed that LGALS3BP is expressed by the vast majority of classical and patient-derived neuroblastoma cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…However, recent studies have revealed that ADCs can also be generated using non-internalizing antibodies [ 26 ], targeting the tumor or its stroma [ 27 , 28 , 29 ]. In the present study, we investigated the therapeutic potential of an ADC targeting exosomal LGALS3BP, consisting of 1959-sss, an engineered humanized anti-LGALS3BP antibody, where the residual cysteines of the light chains was directly coupled to the maytansinoid SH-DM3, through formation of a disulfide bridge [ 30 ]. DM3 is a chemical derivative of maytansine belonging to the tubulin- binding ADC payload class with a cell killing potency in the picomolar range [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

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Targeting Vesicular LGALS3BP by an Antibody-Drug Conjugate as Novel Therapeutic Strategy for Neuroblastoma

Capone

Lamolinara

Pastorino

et al. 2020

Cancers

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Neuroblastoma is the most common extra-cranial solid tumor in infants and children, which accounts for approximately 15% of all cancer-related deaths in the pediatric population. New therapeutic modalities are urgently needed. Antibody-Drug Conjugates (ADC)s-based therapy has been proposed as potential strategy to treat this pediatric malignancy. LGALS3BP is a highly glycosylated protein involved in tumor growth and progression. Studies have shown that LGALS3BP is enriched in extracellular vesicles (EV)s derived by most neuroblastoma cells, where it plays a critical role in preparing a favorable tumor microenvironment (TME) through direct cross talk between cancer and stroma cells. Here, we describe the development of a non-internalizing LGALS3BP ADC, named 1959-sss/DM3, which selectively targets LGALS3BP expressing neuroblastoma. 1959-sss/DM3 mediated potent therapeutic activity in different types of neuroblastoma models. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative. These results offer preclinical proof-of-concept for an ADC targeting exosomal LGALS3BP approach for neuroblastomas.

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Section: Resultssupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting Vesicular LGALS3BP by an Antibody-Drug Conjugate as Novel Therapeutic Strategy for Neuroblastoma

Capone

Lamolinara

Pastorino

et al. 2020

Cancers

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“…(2) Galectin-3-binding protein has scavenger receptor activity, promotes integrin-mediated cell adhesion, and may stimulate host defense against viruses and tumor cells. Significant upregulation in serum or tumor tissue correlates with poor clinical outcomes in melanoma patients [36][37][38], and its inhibitors have potential as antimetastatic cancer drugs [39]. (3) Prothrombin plays a role in blood homeostasis, inflammation, and wound healing.…”

Section: B16 Melanoma-bearing Micementioning

confidence: 99%

Dynamic changes in the urine proteome of tumor-bearing mouse models of B16 melanoma and RM-1 prostate cancer

Pan

Liu

et al. 2020

Preprint

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Urine can accumulate changes and reflect early physiological and pathological changes of various diseases, such as tumors. Therefore, urine is an ideal source for identification of early biomarkers. In this study, melanoma and prostate cancer-bearing mouse models were established by subcutaneous injection of B16 and RM-1 cells, respectively. Urine samples were collected at four time points during tumor growth. Based on dataindependent acquisition (DIA) technology, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for quantitative analysis. Compared with those before the injection of B16 cells, 38 human homologous differential proteins were identified, and 18 proteins were reported to be related to melanoma. Before the tumor was visible, there were 4 differential proteins, and all were reported to be related to melanoma. Compared with that before the injection of RM-1 cells, a total of 14 human homologous differential proteins were identified, and 9 proteins were reported to be associated with prostate cancer. Before the tumor was palpable, 9 proteins showed significant differences. There were significant differences between the two tumor-bearing models. Through the above experiments and analysis, we found that the urine proteome can reflect the changes in the development and provide early biomarkers of the two tumors and provide clues for the early clinical diagnosis of these diseases.Skin melanoma is one of the most common cancers in the world [1]. Melanoma is produced by the malignant transformation of melanocytes. This disease can occur in any part of the skin and mucous membranes. Melanoma easily metastasizes and is highly invasive and malignant, leading to high mortality. The diagnosis of melanoma is based on a combination of clinical and pathological techniques, including physical examination, histopathological examination and imaging examination. However, due to its variable histological morphology, with little or even no visible pigment, it is difficult to diagnose patients in the early stage and distinguish this condition from benign nevus in the clinic, which makes its early diagnosis difficult [2]. Early treatment of melanoma is mainly surgery, and advanced treatment includes chemotherapy, targeted therapy and immunotherapy. Compared with chemotherapy alone, targeted therapy and immunotherapy have significantly improved the survival rate of patients with advanced melanoma, but these two therapies are usually limited by the drug resistance rate and are not universally applicable [3,4]. The absolute survival rate of patients is still very low [5]. The 5-year survival rates of skin melanoma at stage I to IV are 97% (stage IA), 84% (stage IB), 68%, 55%, and 17% [6]. Therefore, early diagnosis can lead to early treatment and improve the survival rate of patients.Prostate cancer is one of the most common malignant tumors in men. In Europe and America, the incidence rate is highest among those of all cancers in males. The mortality rate is second only to that of lung cancer, ranking second fo...

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Extracellular LGALS3BP: a potential disease marker and actionable target for antibody–drug conjugate therapy in glioblastoma

et al. 2023

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Glioblastoma multiforme (GBM) is a lethal disease characterized by an overall survival of about 1 year, making it one of the most aggressive tumours, with very limited therapeutic possibilities. Specific biomarkers for early diagnosis as well as innovative therapeutic strategies are urgently needed to improve the management of this deadly disease. In this work, we demonstrated that vesicular galectin‐3‐binding protein (LGALS3BP), a glycosylated protein overexpressed in a variety of human malignancies, is a potential GBM disease marker and can be efficiently targeted by a specific antibody–drug conjugate (ADC). Immunohistochemical analysis on patient tissues showed that LGALS3BP is highly expressed in GBM and, compared with healthy donors, the amount of vesicular but not total circulating protein is increased. Moreover, analysis of plasma‐derived extracellular vesicles from mice harbouring human GBM revealed that LGALS3BP can be used for liquid biopsy as a marker of disease. Finally, an ADC targeting LGALS3BP, named 1959‐sss/DM4, specifically accumulates in tumour tissue, producing a potent and dose‐dependent antitumor activity. In conclusion, our work provides evidence that vesicular LGALS3BP is a potential novel GBM diagnostic biomarker and therapeutic target deserving further preclinical and clinical validation.

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Secreted Gal-3BP is a novel promising target for non-internalizing Antibody–Drug Conjugates

Cited by 33 publications

References 39 publications

Targeting Vesicular LGALS3BP by an Antibody-Drug Conjugate as Novel Therapeutic Strategy for Neuroblastoma

Targeting Vesicular LGALS3BP by an Antibody-Drug Conjugate as Novel Therapeutic Strategy for Neuroblastoma

Dynamic changes in the urine proteome of tumor-bearing mouse models of B16 melanoma and RM-1 prostate cancer

Extracellular LGALS3BP: a potential disease marker and actionable target for antibody–drug conjugate therapy in glioblastoma

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