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Neuroendocrine cancer targeted therapy

A sequence and antibody technology, applied in the field of neuroendocrine cancer targeted therapy, can solve the problem of non-existent curative treatment of metastatic NE cancer

Pending Publication Date: 2021-08-17
UAB RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, there is no curative treatment for metastatic NE cancer other than surgery

Method used

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  • Neuroendocrine cancer targeted therapy
  • Neuroendocrine cancer targeted therapy
  • Neuroendocrine cancer targeted therapy

Examples

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example 1

[0146] Example 1: Overall Design

[0147] Most NE cancers overexpress the somatostatin receptor (SSTR), with the SSTR2 subtype found predominantly on the cell surface in 70-100% of NE tumors (Pinchot SN et al., Oncologist 2008 13(12):1255- 6; Zatelli MC et al., J Clin Endocrinol Metab. 200186(5):2161-9; SunLC et al., Curr Drug Deliv. 20118(1):2-10 ). More precisely, the surface expression level of SSTR2 in NETs was approximately 20-fold higher than that in normal cells (Pinchot SN et al., Oncologist 2008 13(12):1255-6; Zatelli MC et al. J Clinical Endocrinology & Metabolism 200186(5):2161-9; Sun LC et al, Current Drug Delivery 20118(1):2-10). Therefore, anti-SSTR2 monoclonal antibodies and antibody-drug conjugates (ADCs) have been developed as NE cancer-targeted therapeutics that modulate tumor progression and deliver cytotoxic agents directly to SSTR2-expressing NET cells while limiting systemic Sexual toxicity ( figure 1 ).

[0148] Targeted therapies such as monoclonal...

example 2

[0152] Example 2: Generation of antibody drug conjugates (ADCs) specifically targeting NETs.

[0153] Surface receptor recognition and assessment: Quantification of SSTR2 at the transcriptional level detected higher SSTR2 expression in pancreatic NET (PanNET) cells (BON) than in non-cancerous cells (WI38 fibroblasts) ( Figure 2A ). Additionally, Western blot analysis of PanNETs (BON and QGP), lung NETs (H727) and non-cancer cells (917 and WI38 fibroblasts) confirmed high SSTR2 expression in NE cancers but little expression in non-cancer cells ( Figure 2B ). Using confocal laser scanning microscopy (CLSM) and high-affinity polyclonal antibodies, we determined the strong membrane positivity of SSTR2 in BON cells, BON xenografts, and PanNET human tissues ( Figure 2C ).

[0154]Anti-SSTR2 mAb Development: There are no commercially available anti-SSTR2 mAbs that target surface SSTR2 for therapeutic purposes. To achieve high-affinity and specific binding to NET cells, we used...

example 3

[0157] Example 3: In vitro assessment of ADC anti-NET toxicity and mechanisms.

[0158] Evaluation of NET-specific targeting and anti-NET properties of mAbs: In vivo imaging system (IVIS) confirms that AF488-labeled anti-SSTR2 mAb specifically targets NET subcutaneous xenografts derived from BON-Luc cells ( Figure 3A ). Flow cytometry analysis showed that the mAb had very strong surface binding (99.7%) to BON cells ( Figure 3B ). Therefore, our novel anti-SSTR2 mAb has great potential as a drug delivery vehicle in the form of ADC. Western blot showed that the mAb downregulated PI3K / AKT (cell proliferation), cyclin D1 (oncogene), and p21 (cell cycle arrest), and significantly decreased the expression of CgA and ASCL1 (NET markers) ( Figure 4A ). Using flow cytometry, we analyzed the effect of our SSTR2 mAbs on the expression of cytokines in CD3 / CD28 stimulated human CD8+ T cells after 2 days of incubation with the mAbs. Such as Figure 4B As shown, SSTR2 mAb increased ...

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Abstract

A majority of neuroendocrine (NE) cancers overexpress somatostatin receptors (SSTRs). Disclosed herein are anti-SSTR2 monoclonal antibodies, and antibody-drug conjugates (ADCs) for use as NE cancer targeting therapeutics. Also disclosed is an isolated nucleic acid encoding the disclosed antibodies, as well as nucleic acid vectors containing this isolated nucleic acid operably linked to an expression control sequence. Also disclosed are cells transfected with these vectors and the use of these cells to produce the disclosed recombinant antibodies. Also disclosed is a method of treating a neuroendocrine (NE) cancer in a subject, comprising administering to the subject an effective amount of the disclosed antibody conjugated to an anti-cancer agent.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 742,567, filed October 8, 2018, which is hereby incorporated by reference in its entirety. [0003] sequence listing [0004] This application contains a Sequence Listing filed electronically as an ASCII.txt file named "222104_2890_Sequence_Listing_ST25" created on October 8, 2019. The contents of said Sequence Listing are incorporated herein by reference in their entirety. Background technique [0005] Neuroendocrine (NE) carcinomas such as carcinoids, islet cell tumors, and medullary thyroid carcinoma (MTC) frequently metastasize to the liver (Adler JT et al., Oncologist. 2008 13(7):779-93; Pinchot SN et al., Curr Opin Investig Drugs. 20089(6):576-82; Chen H et al., J Am Coll Surg. 1998187(1):88-92; Chen H et al., J Gastrointest Surg. 19982(2):151-5; Chen H et al., J Surg Oncol. 200897(3):203-4). They are the second most prevalent GI maligna...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/00A61K39/00A61K39/395A61K38/00C12P21/08
CPCA61K47/6849A61K47/6889A61P35/00C07K16/2869C07K2317/77C07K2317/76C07K2317/73C07K2317/34C07K2317/33C07K2317/90A61K2039/505A61K47/68031A61K45/06
Inventor 刘晓光周彔方区健发司英男蕾娜塔·雅斯库拉-斯图尔赫伯特·陈杰森·D·惠特张建宜
Owner UAB RES FOUND
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