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RP215

Humanized monoclonal antibody against cancer-specific antigen CA215

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  • Mechanism of Action
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Drug Name RP215
Description

The monoclonal antibody RP215 was generated against OC-3-VGH ovarian cancer cell extract. It was shown to recognize carbohydrate-associated (O-glycan) epitope(s) of a cancer-cell expressed glycoprotein, designated as CA215, located in the variable regions of heavy chain immunoglobulins. CA215 is only expressed on the surface of cancer cells from the ovary, cervix, lung, and liver, but absent on normal cells.

In vivo experiments have demonstrated RP215 to be an ideal candidate of an anti-cancer drug or a therapeutic treatment.

In addition, RP215-based enzyme immunoassay kits were developed and can be beneficial in monitoring serum level of CA215 among cancer patients.

Indication Cancer
Target CA215
Product Category Monoclonal antibody therapy; Cancer immunotherapy
Mechanism of Action RP215 recognizes CA215 expressed by tumor cells. RP215 has been shown to induce apoptosis and complement-dependent cytotoxicity (CDC) reactions to cancer cells.
Status Preclinical
Patent 7 patents have been granted on RP215 monoclonal antibody worldwide.

Collaboration Opportunity

Protheragen Inc. is actively seeking partnership to further develop RP215. Potential collaboration can be strategic alliance, licensing, or marketing agreement.

We look forward to hearing from you.

CA215

Introduction

CA215, a cancer-associated antigen with molecular weight of approximately 60 KDa, has not yet been developed for medical use. This antigen was initially identified by a monoclonal antibody RP215. With RP215 as the probe, CA215 may be developed to monitor patients with cancer, including those of ovary, cervix, breast, lung, endometrium, stomach, colon, and esophagus.

The carbohydrate-associated epitopes of CA215 with pH-sensitive immunoactivity appear to be present only on cancer cell-derived, not non-pathological, immunoglobulins. Compared to normal immunoglobulin G, CA215 contains a significantly higher percentage of N-acetyl and N-glycoylneuraminic acid in the O-linked glycans, and a lower percentage of N-acetylglucosamine in the N-linked ones.

Molecular Size 50 to 70 KDa
Expression Form Both secreted and membrane-bound monomeric forms
Location The variable domain of human immunoglobulin heavy chains

Clinical Resources

Major Conditions Cancer

Cancer Cells Expressing CA215

Extensive IHC studies were performed on cancer cells of different human tissues. As shown in table below, cancer tissues from ovary, cervix, endometrium, stomach, esophagus and colon revealed greater than 50% of positive staining using RP215 monoclonal antibody. Breast and lung cancer tissues exhibited only 30-35% of positive staining. Benign ovarian tumor specimens gave a significantly lower percentage of positive staining by ovary.

Summarized results of immunohistochemical staining of cancer tissues in humans
Cancer tissues (Case No.) Positive cases Negative cases Percentage positive (%)
Ovary (87) 56 31 64.4
Cervix (51) 43 8 84.3
Endometrium (36) 28 8 77.8
Stomach (93) 46 47 49.5
Colon (87) 38 49 43.6
Esophagus (56) 40 16 75.7
Lung (58) 18 40 31
Breast (59) 19 40 32.2
Liver (60) 2 58 3.5
Prostate (22) 2 20 9.1
Ovary (Benign) (31) 2 29 6.5
Cervix Cancer

Cervical cancer, the malignant tumor of the uterine cervix, is one of the most serious causes of cancer morbidity and mortality among women worldwide. The International Agency for Research on Cancer (IARC) estimated that 569,847 cases of cervical cancer were diagnosed worldwide in 2018. Squamous cell carcinomas arising from the metaplastic squamous epithelium of the cervical transformation zone account for approximately 70% of all cases of cervical cancer. Cervical adenocarcinomas arising from the columnar epithelium of the endocervix account for 25% of the cases in the U.S., and the number is increasing. Adenosquamous carcinoma, the least common form, accounts for 3-5% of all cases.

Invasive cervical carcinoma requires aggressive and often multicomponent therapy including surgery, external-beam radiation, brachytherapy, and chemotherapy. Typically, early cervical cancer is treated surgically, while concurrent chemoradiotherapy is the preferred modality for locally advanced cervical cancer.

Endometrial Cancer Endometrial cancer (EC) originates in the endometrium, the inner lining of the body of the uterus (corpus uteri), and is classified into type I or type II. EC is the fifth most common cancer in women worldwide and continues to increase in both incidence (by 1-2% yearly) as well as prevalence. Although the prevalence of endometrial cancer is high, the mortality-to-incidence ratio is lower than that of other gynecological malignancies. Most patients do well with surgery alone. Five-year survival rates for women with FIGO stage I-II endometrial cancer range from 74% to 91%.
Esophageal Cancer

Esophageal cancer refers to a malignant tumor of the esophagus which is the tube that connects the throat with the stomach. The two main sub-types of the disease are esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Esophageal cancer is the eighth most frequently diagnosed cancer worldwide. Because of its poor prognosis, it is the sixth most common cause of cancer-related death.

In general, a combined approach that includes surgery may be considered as a curative intention of localized esophageal cancer. In the case of disease that is widespread and metastatic, chemotherapy may be used to lengthen survival, while treatments such as radiotherapy or stenting may be used to relieve symptoms and ease swallowing.

Ovarian Cancer

Ovarian cancer typically spreads via local shedding into the peritoneal cavity, followed by the implantation of high-grade papillary serous tumors on the peritoneum and local invasion of the bowel and bladder. The cancer spreading to pelvic lymph nodes is also common and it increases with the stages of disease. According to Globocan data for 2018, the global incidence of ovarian cancer would be 295,414, and the five-year survival rate in average is 30-40%.

At present, the two main ovarian cancer therapies are surgery and chemotherapy, alone or in combination depending upon the characteristics of individual patient and tumor.

RP215 Recognizes CA215 and Induces Lysis and Apoptosis of Cancer Cells.

Immunoglobulin expressed on the surface of most cancer cells may be a specifically recognized target of RP215. Biological and immunological studies have also shown that RP215 can induce apoptosis of cancer cells, as well as the CDC response in the presence of complement. This response induces cleavage of cultured cancer cells. As demonstrated by experiments using several nude mouse models, within a certain range, increased dosage of RP215 significantly reduced the tumor volume.

Two strategies can potentially be used to developing anti-cancer drugs from RP215. One is passive immunity by humanized RP215 to treat cancer patients. The other is CAR-T cell therapy. Humanized RP215 gene in the Fab domain can be packaged in the vector in the form of chimeric antigen receptor (CAR).

The Patent Status of RP215

7 patents have been granted worldwide on RP215 monoclonal antibody and the relevant use.

* and ** represent statistical significance of P<0.01 and P<0.001, respectively as compared to the normal IgG control.

Percentage induced apoptosis of cultured cancer cells following treatment and TUNEL assay.

A.Percent induced apoptosis of OC-3-VGH ovarian cancer cells following 24hrs incubation with various antibodies. Antibodies were added separately for 24hrs incubation by including 10μg/mL and 1μg/mL of normal mouse IgG (NMIgG), normal human IgG (NHIgG), murine RP215 (MRP215), humanized RP215 (HRP215) and goat anti-human IgG, respectively.

B. Percent induced apoptosis following treatment of various cultured cancer cell lines with NMIgG or MRP215. This figure demonstrates the effect of normal NMIgG and MRP215 on various cancer cell lines, including DU-145 (prostate), A549 (lung), C33A (cervix), and OC-3-VGH (ovary).


* and ** represent statistical significance of P<0.01 and P<0.001, respectively.

Complement-dependent cytotoxicity assay to demonstrate complement-dependent lysis of OC-3-VGH ovarian cancer cells using different treatments in the presence or absence of complement.

C represents complement. Negative controls include no treatment (control) and complement only (C). Treatments, which resulted in a significant percentage of lysis, include HRP215+C, murine RP215 plus MRP215+C, and goat anti-human IgG plus complement (GAHIgG+C), respectively.


* and ** represent statistical significance of P<0.01 and P<0.001, respectively.

Nude mice experiments to demonstrate dose-dependent effect of injected RP215 on implanted tumor volumes.

A. Effect of injected RP215 on nude mice inoculated with OC-3-VGH ovarian cancer cell line. On day 0, mice were inoculated with OC-3-VGH cancer cells (1 x 107 cells/mouse). On the same day, mice (n = 4 for each group) either received no treatment (negative control), or were injected with drug treatment of 60mg/kg cyclophosphamide (positive control), 10mg/kg RP215 (antibody high dose), or 2mg/kg RP215 (antibody low dose). Tumor volumes were determined on day 15.

B. Effect of injected RP215 on nude mice inoculated with SK-MES-1 squamous lung cancer cells. On day 0, mice were inoculated with tumor cells. After four weeks, mice were randomized into 4 groups (n = 5 for each group) and injected with phosphate buffered saline (negative control) or treatment (positive control, RP215 of high (0.75 mg/mouse) or low (0.14 mg/mouse) dose). Mice were injected with Gemcitabine and Cisplatin of each dose as positive control. Treatment in all four groups were repeated on week 5. On week 6, tumors were removed to measure the volume.

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