Monoclonal antibodies
MULTIPLE MYELOMA

Disease Background
Myeloma is a cancer of the plasma cells in the bone marrow, the spongy tissue inside of bones. Plasma cells are a part of the body's immune system and produce antibodies that help the body fight infection. Abnormal plasma cells can suppress the growth of other cells in the bone marrow that produce red blood cells, white blood cells, and platelets. This suppression may result in anemia (from a shortage of red blood cells), excessive bleeding from cuts (from a shortage of platelets), and a decreased ability to fight infection (from a shortage of white blood cells and the body’s inability to respond to infection normally).

Myeloma often causes structural bone damage resulting in painful fractures. Myeloma is often called multiple myeloma because most people (90%) have multiple bone lesions at the time it is diagnosed.

The global multiple myeloma (MM) market was valued at $2,347m in 2009 and is forecast to grow at a CAGR of 10.4% for the next seven years, to reach $5,185m by 2017. The growth will primarily be driven by an increase in the disease incidence rate, an increase in awareness of the treatment options, an increase in the treatment seeking population, and the acceptance of the existing therapies.


Therapy

Most myeloma cells will eventually become resistant to standard chemotherapy, a condition called multidrug resistance. New drugs and combinations of approved drugs are being researched to provide more options for patients with myeloma. Several drug combinations are being studied:

Thalidomide, bortezomib, and dexamethasone
Bortezomib and lenalidomide
Boretzomib, lenalidomide, and dexamethasone



Scientific Rationale & Progress
TBL-0306M is a unique monoclonal antibody based drug developed by the scientists of TBL as a result of continuous efforts from 2004 onwards.

TBL-0306M that has demonstrated excellent in-vitro efficacy and the data is the cornerstone for TBL to advance this drug to the next stage in the drug development program.

TBL-0306M is chimerized and now undergoing humanization after which it will undergo pre-clinical in-vivo studies.
NON-HODGKIN’S LYMPHOMA

Disease Background
NHLs are tumors originating from lymphoid tissues, mainly of lymph nodes.The term lymphoma describes a heterogeneous group of malignancies with different biology and prognosis. In general, lymphomas are divided into 2 large groups of neoplasms, namely non-Hodgkin lymphoma (NHL) and Hodgkin disease. About 85% of all malignant lymphomas are NHLs.

The incidence of non-Hodgkin lymphoma (NHL) increases with increasing age. The highest incidence is among people aged 80 years and over.NHL is the most prevalent hematopoietic neoplasm, representing approximately 4% of all cancer diagnoses and ranking seventh in frequency among all cancers.

The causes of non-Hodgkin’s lymphomas are not known. A malfunctioning immune system may be involved, as a result of HIV infection, or exposure to chemotherapy or drugs designed to suppress the rejection of organ transplants. It is also suspected that lymphocyte damage from certain viral infections such as HTLV or the Epstein-Barr Virus may play a part. NHLs may also result from chromosomal translocations, environmental factors, immunodeficiency states, and chronic inflammation.

GlobalData estimated the global Non-Hodgkin's Lymphoma (NHL) market to be worth $6.5 billion in 2009 and forecasted to grow at a compound annual growth rate (CAGR) of 7.74% annually to reach $11.9 billion by 2017.


Therapy
Standard management consists of radiotherapy alone.Frequently used combination regimens are CHOP (cyclophosphamide, hydroxydaunomycin [Adriamycin], vincristine [Oncovin], and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and fludarabine alone or in combination (eg, with cyclophosphamide or mitoxantrone). These chemotherapy drugs may result in significant side effects.

The treatment of indolent B-cell lymphomas continues to evolve as new therapies with potent antitumor activity and limited toxicity are becoming available. Monoclonal antibodies are changing the treatment paradigm of patients with B-cell lymphomas.


Scientific Rationale & Progress
TBL-0306L is a unique monoclonal antibody based drug developed by the scientists of TBL as a result of continuous efforts from 2004 onwards.

TBL-0306L that has demonstrated excellent in-vitro efficacy and the data is the cornerstone for TBL to advance this drug to the next stage in the drug development program.

TBL-0306L is chimerized and now undergoing humanization after which it will undergo pre-clinical in-vivo studies.

Because of its specific target on the cells involved in NHL, TBL-0306L is potentially an excellent drug of choice.
COLORECTAL CANCER

Disease Background
Colorectal cancer is the third most common cancer in men (663 000 cases, 10.0% of the total) and the second in women (571 000 cases, 9.4% of the total) worldwide. About 608 000 deaths from colorectal cancer are estimated worldwide, accounting for 8% of all cancer deaths, making it the fourth most common cause of death from cancer.

It has been observed that substantial regional and ethnic variations in colorectal cancer incidence trends within countries such as Japan, Israel, and Singapore. Many of the established and suspected modifiable risk factors for colorectal cancer, including obesity, physical inactivity, smoking, heavy alcohol consumption, a diet high in red or processed meats, and inadequate consumption of fruits and vegetables, are also factors associated with economic development or westernization.

According to an article published in the European Journal of Cancer, tumor location impacts colon cancer survival rate. According to the same study, colon cancer survival rates also vary by country. While the overall five-year survival for colon cancer in America is 62%, it's 43% in Europe. Quality of care may be one reason, but another could be colon cancer screening programs. In general, the earlier colon cancer is detected, the easier it is to treat.

Stage at diagnosis also greatly impacts colon cancer survival rates. Research published in the ANZ Journal of Surgery found that In Australia, the five-year survival for stage 1 colon cancer is 93%, but it drops to 59% for stage 3 colon cancer.


Therapy
The problem with traditional chemotherapy is that it can't be focused. The drugs go through the body, affecting both cancerous cells and healthy cells alike.

Monoclonal antibodies are a new generation of cancer drugs that can specifically target defects that allow cancer cells to proliferate, and as a result, typically have fewer side effects. They include bevacizumab (Avastin), cetuximab (Erbitux) and panitumumab (Vectibix). Targeted drugs are typically reserved for people with advanced colon cancer, and can be given along with chemotherapy or alone. Some people are helped by targeted drugs, while others are not. Researchers are working to determine who is most likely to benefit from targeted drugs.

Avastin is modeled after the antibodies that naturally protect the body. It blocks the effects of a substance in the blood that helps tumors grow new blood vessels. This substance is called vascular endothelial growth factor (VEGF.) By preventing the creation of new blood vessels in the tumor, the cancer is "starved." Erbitux blocks the effects of a different growth factor called epidermal growth factor (EGF).

There are some drawbacks to these new drugs however. For one, they are both only approved for people with metastatic cancer. They haven't yet been shown to work in earlier stages of the disease. And, they are still associated with side effects. In addition, Avastin seems to increase the risk of heart attacks and strokes, which makes it unsafe for some people, and prompted the FDA to request an additional warning to be added to the product labeling.


Scientific Rationale & Progress
TBL-0306C is a monoclonal antibody raised against and binds specifically to a genetically engineered peptide encoding an epitope on the Tumor necrosis factor receptor super family. The main focus of TBL-0306C is to selectively target and kill Colon cancer cells by monoclonal antibodies produced against a unique surface antigen over expressed on Colon cancer. Because of its high specificity, the drug has so far demonstrated excellent efficacy in killing the cancer cells while showing nil or minimal effect on the normal cells.

TBL-0306C is now progressing through humanization, and will advance to pre-clinical trials shortly.
ESOPHAGEAL CANCER – BARRETT’S ADENO-CARCINOMA

Disease Background
Esophageal cancer is the eighth most common cause of cancer death worldwide. There are two main histological types; squamous cell carcinoma (SCC) and adenocarcinoma (ADC). Worldwide, SCC is the predominant histological type. Adenocarcinoma is mainly a disease of developed countries.

Squamous cell carcinoma of the esophagus remains predominantly a disease of the developing world. In contrast, esophageal adenocarcinoma is mainly a disease of western developed societies, associated with obesity and gastro-esophageal reflux disease. There has been a dramatic increase in the incidence of adenocarcinoma in developed countries in parallel with migration of both esophageal and gastric adenocarcinomas towards the gastro-esophageal junction.

Adenocarcinoma of the esophagus, different from squamous cell carcinoma, affects the distal esophagus of young patients and is usually detected in an early stages.

Esophageal cancer (EC) is a devastating disease. Although some patients can be cured, the treatment for esophageal cancer is protracted, decreases quality of life, and is lethal in a significant number of cases.

The prognosis of esophageal cancer is still poor, as these cancers are found late.

GlobalData estimates that the global esophageal cancer therapeutics market was valued at $243.8m in 2010, and is forecast to grow at a Compound Annual Growth Rate (CAGR) of 14% over the next seven years, to reach $594.7m by 2017.


Therapy
The esophageal cancer therapeutics market is represented by Herceptin and some off-label drugs. Cisplatin, Xeloda (capecitabine) and ECF are mainly used drugs for treating esophageal cancer.


Scientific Rationale & Progress
TBL-0805E is the result of several years of intense research at Transgene. TBL-0805E is a novel monoclonal antibody targeted specifically at the Esophageal adeno-carcinoma.

The developed mAb has been chimerized and in-vitro efficacy studies are being carried out to compare its earlier efficacy prior to chimerization and on its progress towards humanization.

Once the in-vitro cytotoxicity assays are completed TBL 0805E shall advance to in-vivo studies.
 
 
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