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Monoclonal antibody neo-201 for the treatment of human carcinomas

A NEO-201, antibody technology, applied in the field of monoclonal antibody NEO-201 for the treatment of human cancer, can solve problems such as side effects, patients with incurable advanced diseases, recurrence, etc.

Pending Publication Date: 2020-09-15
精密生物制品股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Conventional methods of treating cancer such as surgery, radiation, and chemotherapy frequently induce severe side effects and fail to cure most patients with advanced disease, resulting in relapse (Bodey et al., 1996)

Method used

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  • Monoclonal antibody neo-201 for the treatment of human carcinomas
  • Monoclonal antibody neo-201 for the treatment of human carcinomas
  • Monoclonal antibody neo-201 for the treatment of human carcinomas

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0139] NEO-201 binds to various human cancer cell lines

[0140] Flow cytometry analysis was used to profile NEO-201 binding on a panel of human cancer cell lines. Staining profiles are summarized in Table 1, and representative histograms from cell lines with high, medium, low and negative staining are in Figures 1A-1Cshown in . Evaluation of the binding activity of NEO-201 revealed that 3 / 6 (50%) colon cancer cell lines and 4 / 5 (80%) pancreatic cancer cell lines were highly positive. When profiling non-small cell lung cancer (NSCLC) cell lines of various histological subtypes, it was determined that 3 / 5 (60%) of the adenocarcinoma cell lines responded to NEO-201, while only 1 / 4 (25 %) squamous cell carcinoma cell lines were found positive. Screening of breast cancer cell lines was also performed. Among cell lines expressing estrogen receptor (ER) or progesterone receptor (PR), 2 / 4 (50%) stained positive for NEO-201, either alone or in combination with HER2. Among HER2+ ...

Embodiment 2

[0142] NEO-201 tissue staining is highly tumor-specific

[0143] NEO-201 reactivity from human tumor samples was investigated using immunohistochemical studies using tissue microarrays representing many samples of each cancer type. Such as Figure 2A As shown, immunoreactivity 7,829,678 with NEO-201 was completely absent in normal colon, pancreas, and lung tissues, but was highly positive in tumor tissues from these organs. Strikingly, staining was found only on tumor cells, as surrounding stromal cells were not stained ( Figure 2A ). IHC staining of microarray samples identified NEO-201 against colon cancer (72%), pancreatic cancer (80%), gastric cancer (71%), lung cancer (61%), breast cancer (55%) and uterine cancer (54%) Highly reactive. In addition, a considerable minority of ovarian cancer (26%) samples also showed positive staining, but in prostate cancer tissues ( Figure 2B ) No staining was observed. Overall, 258 / 345 (74.7%) of the sampled tumor tissues stained...

Embodiment 3

[0145] NEO-201 mediates ADCC and CDC to kill tumor cells

[0146] As a humanized IgG1 antibody, NEO-201 can theoretically mediate ADCC to kill tumor cells expressing NEO-201 antigen. To investigate this potential mechanism of action, a cell line that stained highly positive for NEO-201 was subjected to an ADCC assay utilizing human natural killer (NK) cells isolated from PBMCs from two different healthy donors (CFPAC-1 and ASPC-1). It was observed that treatment with NEO-201 enhanced the killing of CFPAC-1 and ASPC-1 to a level that was 2- to 6-fold greater than that of control IgG1-treated tumor cells ( Figure 3A ). Titration experiments were also performed and revealed that NEO-201 retained a significant ability to induce ADCC at doses as low as 0.1 μg / mL ( Figure 3B ).

[0147] CDC is a complex cascade of proteolytic cleavage culminating in activation of the membrane attack complex, which lyses antibody-bound target cells. Certain human IgG1 antibodies are capable of...

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Abstract

NEO-201 is a humanized IgG1 monoclonal antibody (mAb) that is highly reactive against the majority of tumor tissues from many different carcinomas, including colon, pancreatic, stomach, lung, breast,and uterine cancers, but the overwhelming majority of normal tissues are not recognized by this antibody. Functional assays revealed that NEO-201 is capable of mediating both antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against tumor cells. Furthermore, the growth of human pancreatic xenograft tumors in vivo was largely attenuated by treatment with NEO-201 both alone and in combination with human peripheral blood mononuclear cells (PBMC) as an effector cell source for ADCC. In vivo biodistribution studies in human tumor xenograft-bearing mice revealed that NEO-201 preferentially accumulates in the tumor but not organ tissue. A single-dose toxicity study in non-human primates demonstrated safety and tolerability of NEO-201, as a transient decrease in circulating neutrophils was the only related adverse effect observed.

Description

[0001] Related Application Disclosures [0002] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 592,778, filed November 30, 2017, and U.S. Provisional Application Serial No. 62 / 581,380, filed November 3, 2017, each of which is hereby incorporated by reference in its entirety incorporated. [0003] Sequence Listing Information [0004] This application includes as part of its disclosure a biological sequence listing in the form of a file named "43282o4402.txt", created on November 2, 2018, with a size of 32,563 bytes, said biological sequence listing It is hereby incorporated by reference in its entirety. Background technique [0005] Cancer represents one of the most common causes of death worldwide, with an estimated 20 million new cases per year expected as early as 2025 (Ferlay et al., 2015). Conventional methods of treating cancer such as surgery, radiation, and chemotherapy frequently induce severe side effects and fail to cure the maj...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28A61K39/395
CPCC07K16/30A61K2039/505C07K2317/30C07K2317/732C07K2317/734C07K2317/90C07K16/2803A61K39/39558A61K38/2086A61K38/05A61K38/2013A61K38/20A61K38/1725A61K45/06A61P35/00A61K2300/00C07K2317/21C07K2317/24
Inventor P·M·阿兰K·Y·曾
Owner 精密生物制品股份有限公司
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