1. TARGETED AND BIOLOGICAL THERAPY OF CANCER PHL 417
1/1/2015
DR. Mohamed M. Sayed-Ahmed
TARGETED AND BIOLOGICAL THERAPY OF CANCER PHL 417
PHL 425

2. 1- Monoclonal Antibody Drugs For Cancer Treatment
What is a monoclonal antibody:
A monoclonal antibody is a laboratory-produced molecule that's carefully engineered to attach to specific defects in your cancer cells. Monoclonal antibodies mimic the antibodies your body naturally produces as part of your immune system's response to germs, vaccines and other invaders.

3. How do monoclonal antibody drugs work
1- Make the cancer cell more visible to the immune system.
The immune system attacks foreign invaders in your body, but it doesn't always recognize cancer cells as enemies. A monoclonal antibody can be directed to attach to certain parts of a cancer cell. In this way, the antibody marks the cancer cell and makes it easier for the immune system to find.
The monoclonal antibody drug Rituximab attaches to a specific protein (CD20) found only on B cells, one type of white blood cell. Certain types of lymphomas arise from these same B cells. When Rituximab attaches to this protein on the B cells, it makes the cells more visible to the immune system, which can then attack. Rituximab lowers the number of B cells, including your healthy B cells, but your body produces new healthy B cells to replace these. The cancerous B cells are less likely to recur.

4. RITUXIMAB (Rituxan)
A recombinant chimeric murine/human antibody directed against the CD20 antigen, a hydrophobic transmembrane protein located on normal pre-B and mature B lymphocytes.
Following binding, rituximab triggers a host cytotoxic immune response against CD20-positive cells.
Rituximab is used in the treatment of B-cell Non-Hodgkin's lymphomas.
MECHANISM OF ACTION:
Complement fixation
ADCC
Direct cytotoxicity via apoptotic pathway activated by binding to CD20.

5. Alemtuzumab (al-em-to-zoo-mab) (MabCampath®) Alemtuzumab is humanized monoclonal antibody that targets CD52, a glycoprotein highly expressed on both B-CLL cells and normal B and T cells. Therefore, CLL seemed the optimal setting for this new agent, as it is primarily a malignancy of the peripheral blood and bone marrow Alemtuzumab (Campath-1H) was approved by the FDA for the treatment of B-cell CLL unsuccessfully treated by alkylating agents and fludarabine. The mechanism of action of alemtuzumab is not well understood, but it is presumed to work via ADCC, CDC, and/or apoptosis.

6. Alemtuzumab-How is it given
MabCampath is given as a drip (infusion) through a fine tube (cannula) inserted into a vein in arm or back of the hand. Each drip takes approximately two hours. It can also be given as an injection under the skin (subcutaneously).
Some people have an allergic reaction to MabCampath. To reduce the risk of a reaction the first few doses are given slowly. You may also be given some antihistamines, paracetamol and sometimes a small dose of steroids before the infusion. These will help to reduce the risk of reactions. If you do have a reaction, the infusion can be stopped and started again once the symptoms are over.
You will be asked to stay in hospital for a few hours after the infusion, or possibly overnight, to be monitored. The dose of MabCampath is increased over a few days until the recommended dose is achieved. This usually takes three to seven days and is known as dose escalation. Once the recommended dose is achieved the treatment is given three times a week (e.g. on Monday, Wednesday and Friday). Most people have treatment for 4–12 weeks.

7. 2- Block growth signals:
Chemicals called growth factors attach to receptors on the surface of normal cells and cancer cells, signaling the cells to grow. Certain cancer cells make extra copies of the growth factor receptor. This makes them grow faster than the normal cells.
Monoclonal antibodies can block these receptors and prevent the growth signal from getting through.

8. Cetuximab Cetuximab (Erbitux), a monoclonal antibody approved to treat colon cancer and head and neck cancers, attaches to Epidermal Growth Factor Receptors (EGFR) on cancer cells that accept a certain growth signal (EGF). Cancer cells and some healthy cells rely on this signal to tell them to divide and multiply. Blocking this signal from reaching its target on the cancer cells may slow or stop the cancer from growing.

9. How Cetuximab Works
Cetuximab attaches itself to the EGFRs and prevents the receptors from being activated. This stops the cells from dividing. It therefore has the potential to stop the cancer cells from growing. It works in a different way from both chemotherapy and hormonal therapy.
Cetuximab may also make the cancer cells more sensitive to chemotherapy.
Tests may be done to find the level of EGFR in the body before cetuximab is given. This can help the doctors to know whether you are likely to benefit from this treatment. Testing can be done at the same time as diagnosis of the cancer, or samples of cancer cells from previous biopsies or surgery may be used.
Cetuximab is given by a drip into the vein (intravenously) through a fine tube (cannula) inserted into a vein. The first dose is given slowly, usually over two hours. After this, doses are given weekly and this normally takes about an hour. The first dose is usually larger than the weekly maintenance treatments. You may be given other medicines before cetuximab to lessen the side effects during treatment.

10. Panitumumab (ABX-EGF)
Panitumumab belongs to a subgroup of monoclonal antibodies, known as epidermal growth factor receptor (EGFR) inhibitors.
Epidermal growth factor (EGF) is a protein that is present in the body. There are receptors for EGF on the surface of many types of cancer cell. When EGF binds to these receptors, chemical signals are triggered which cause the cells to grow and reproduce.
Panitumumab attaches itself to the EGFR, and prevents it from being activated. This stops the internal chemical signalling, and inhibits the growth of cancer cells that have the EGFR on their surface.
Tests may be done to check the level of EGFR present in the tumour; these will tell if you are likely to benefit from panitumumab. Testing can be done at the same time as diagnosis, or samples of cancer cells from previous biopsies, or surgery, may be used.

11. TRASTUZUMAB (Herceptin)
TRASTUZUMAB is a recombinant humanized monoclonal antibody directed against the human epidermal growth factor receptor 2 (HER2).
After binding to HER2 on the tumor cell surface, trastuzumab induces an antibody-dependent cell mediated cytotoxicity (ADCC) against tumor cells that overexpress HER2.
HER2 is overexpressed by many adenocarcinomas, particularly breast adenocarcinomas.

12. This therapy requires the obligation of HER-2 tumour typing following any surgical intervention of an invasive breast cancer.
The activity of trastuzumab is directed against the human epidermal
growth factor receptor-2 (HER-2).
Herceptin® must only be administered to female HER-2-positive
patients, i.e., in whom the tumours overexpress the HER-2 protein or
amplify the HER-2 gene.
Monitoring of HER-2 in tumours is essential: The overexpression of
HER-2 must be searched for using immunohistochemisty (IHC) in
embedded tumour fragments, or using genic amplification in situ
hybridisation (FISH1 or CISH2 technique). IHC, the search for genic
amplification must be positive to be able to envisage such

13. 3- Stop new blood vessels from forming:
Cancer cells rely on blood vessels to bring them the oxygen and nutrients they need to grow. To attract blood vessels, cancer cells send out growth signals. Monoclonal antibodies that block these growth signals may help prevent a tumor from developing a blood supply, so that it remains small. Or in the case of a tumor with an already-established network of blood vessels, blocking the growth signals could cause the blood vessels to die and the tumor to shrink.
The monoclonal antibody bevacizumab (Avastin) targets a growth signal called vascular endothelial growth factor (VEGF) that cancer cells send out to attract new blood vessels.

14. BEVACIZUMAB (Avastin)
A recombinant humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF), a pro-angiogenic cytokine.
Bevacizumab binds to VEGF and inhibits VEGF receptor binding, thereby preventing the growth and maintenance of tumor blood vessels.

15. 4- Deliver radiation to cancer cells:
By combining a radioactive particle with a monoclonal antibody, doctors can deliver radiation directly to the cancer cells. This way, most of the surrounding healthy cells aren't damaged.
Radiation-linked monoclonal antibodies deliver a low level of radiation over a longer period of time, which researchers believe is as effective as the more conventional high-dose external beam radiation.

16. 90Y-Ibritumomab (Zevalin)
(90Y) Yttrium-90 (it-ree-um).
90Y-Ibritumomab (Zevalin), approved for non-Hodgkin's lymphoma, combines a monoclonal antibody with radioactive particles.
The ibritumomab monoclonal antibody attaches to receptors on cancerous blood cells and delivers the radiation. Yttrium-90 produces radiation that is strong enough to destroy cancer cells. It can also affect normal cells.
A number of monoclonal antibody drugs are available to treat various types of cancer. Clinical trials are studying monoclonal antibody drugs in treating nearly every type of cancer

17. How zevalin works and given
As Zevalin enters the bloodstream, the monoclonal antibody portion recognises and attaches to the CD20 protein. Energy is then released from the yttrium radioisotope, damaging or killing the B-cell. Zevalin attacks both normal and abnormal (malignant) B-cell lymphocytes. However, the body quickly replaces any normal white blood cells that are damaged, so the risk of side effects from this is very small.
Zevalin is used with Rituximab. Together they lock onto a protein called CD20, which is found on the surface of one of the main types of normal white blood cells (B-cell lymphocytes). CD20 is also present on the surface of most of the abnormal B-cell lymphocytes, which occur in many types of non-Hodgkin lymphoma. The monoclonal antibodies attack both normal and abnormal (malignant) B-cell lymphocytes.

18. How zevalin works and given
Zevalin is given as a single 'one-off' treatment and not as repeated courses of treatment.
It consists of two components, given approximately one week apart: Retuximab and Zevalin
Rituximab is given on the first day of treatment to reduce the number of normal healthy B-cells. This prevents the Zevalin from attaching to and destroying healthy, non-cancerous cells. Rituximab is given as a drip into a vein (intravenous infusion). It is given slowly over a few hours. You will be given some steroids and antihistamines beforehand to reduce the risk of an allergic reaction.
You will receive a second infusion of rituximab about one week after your first dose. Within four hours of this infusion you will go to the nuclear medicine or radiotherapy department to have the Zevalin treatment. This is given by drip and takes about ten minutes.

19. 131I-tositumomab (toss-i-to-mo-mab), (Bexxar)
Nonmyeloablative use of an 131I anti-CD20
murine antibody, is well tolerated and highly effective in the treatment of relapsed or refractory low-grade, follicular, or transformed B-cell NHL (B-NHL). BEXXAR has a radioactive substance called iodine131 attached to it. The monoclonal antibody in BEXXAR, tositumomab, attaches to a protein found on the surface of the B-cells. As a result, the radioactive iodine delivers radiation directly to these cells. This destroys the lymphoma B-cells. Unfortunately it may also affect some normal cells.

20. Gemtuzumab (gem-to-zoo-mab)
Gemtuzumab ozogamicin (GO, Mylotarg) consists of a recombinant, humanized anti-CD33 monoclonal antibody conjugated to calicheamicin, a potent antitumor antibiotic. Within the acidic environment of lysosomes after internalization, calicheamicin dissociates from the antibody and migrates to the nucleus, where it binds within the minor groove of DNA and causes double-stranded DNA breaks.
It is mainly used as part to treat some types of acute myeloid leukaemia (AML).
It carries a chemotherapy drug called ozogamicin directly to the cancer cells. As the chemotherapy is only delivered to cells showing the CD33 protein it may not affect normal cells within the body.

21. FDA-APPROVED MONOCLONAL ANTIBODIES TARGETS and INDICATIONS
Antibody
Trade Name
Target Antigen
FDA Indication
Rituximab
Rituxan
CD20
B-NHL
90Y-Ibritumomab
Zevalin
131I-tositumomab
Bexxar
Alemtuzumab
Campath
CD52
CLL
Gemtuzumab
ozogamicin
Mylotarg
CD33
AML
Cetuximab
Erbitux
EGFR
metastatic
CRC
Panitumumab
ABX-EGF
Trastuzumab
Herceptin
HER2/neu
Metastatic
Br CA

22. FDA-APPROVED MONOCLONAL ANTIBODIES
Rituximab (Rituxan) was the first mAb approved by the FDA in 1997 for the treatment of relapsed or refractory low-grade or follicular CD20-positive B-cell non-Hodgkin's lymphoma (B-NHL).
Alemtuzumab (Campath-1H) was approved by the FDA for the treatment of fludarabine-refractory B-cell CLL.
Patients with metastatic Her-2 Neu overexpressing metastatic breast carcinoma can receive targeted therapy with trastuzumab (Herceptin).
Bevacizumab and cetuximab recently received FDA approval for the treatment of metastatic colorectal carcinoma.
Gemtuzumab ozogamicin (Mylotarg), an antibody-drug conjugate, was approved by the FDA in 2000 for the treatment of CD33-positive, relapsed acute myeloid leukemia (AML) patients
90Y-ibritumomab tiuxetan (Zevalin) was the first radiolabeled antibody approved for cancer therapy. Subsequently, 131I-tositumomab (Bexxar) was approved by the FDA for the treatment of relapsed or refractory low-grade follicular or transformed CD20-positive B-cell NHL.

23. ANGIOGENESIS INHIBITORS

24. ANGIOGENESIS INHIBITORS

25. Angiogenic Factors 2- vascular endothelial growth factor (VEGF)
1- Angiogenin
2- vascular endothelial growth factor (VEGF)
3- Fibroblast growth factor (FGF)
4- Transforming growth factor-β (TGF-β)).
5- platelet derived growrh factor (PDGF)
These stimulate endothelial cell proliferation,
migration and invasion resulting in new vascular
structures sprouting from the patient's blood vessels.
Cell adhesion molecules, such as integrins, are critical
To the attachment and migration of endothelial cells to
The extracellular matrix.

26. Endogenous anti-angiogenic factors
1- Endostatin: It induces apoptosis in endothelial cells
and inhibition of their migration to sites of neovascularisation,
probably by interfering with endothelial cell adhesion
2- Angiostatin: Like endostatin, it directly induces apoptosis of
endothelial cells by disrupting the normal adhesion contacts
between the endothelial cells. Angiostatin also acts by
inhibiting VEGF and basic fibroblast growth factor (bFGF).
3- Interferon-alfa: has an anti-angiogenic effect by inhibiting
endothelial cell migration. It has been successfully used to
treat haemagiomas, refractory giant cell tumours and
angioblastomas.

27. ANGIOGENESIS INHIBITORS

28. ANGIOGENESIS INHIBITORS
1- BEVACIZUMAB (Avastin)
A recombinant humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF), a pro-angiogenic cytokine.
Bevacizumab binds to VEGF and inhibits VEGF receptor binding, thereby preventing the growth and maintenance of tumor blood vessels.

29. 2- NEOVASTAT
A multifunctional antiangiogenic agent derived from shark cartilage with potential antineoplastic activity.
Shark cartilage extract AE-941 competitively inhibits the binding of pro-angiogenic vascular endothelial growth factor (VEGF) to its cell receptor, thereby inhibiting endothelial cell proliferation.
This agent also inhibits matrix metalloproteinases (MMPs), stimulates tissue plasminogen activator (tPA), and activates caspase-mediated apoptotic pathways in endothelial cells.

30. 3- COMBRETASTATIN A4 PHOSPHATE
A water-soluble prodrug derived from the African bush willow (Combretum caffrum) with tumor vascular-targeting activity.
In vivo, combretastatin A4 phosphate is dephosphorylated to its active metabolite, combretastatin A4, which binds to tubulin and inhibits microtubule depolymerization, resulting in morphological changes in proliferating endothelial cells.
As a result, the permeability of tumor vasculature is increased, leading to reduced tumor blood flow and ischemic necrosis of tumor tissue.

31. MATRIX METALLOPROTEINASE INHIBITORS
1- MARIMASTAT
An orally-active synthetic hydroxamate with potential antineoplastic activity. Marimastat covalently binds to the zinc(II) ion in the active site of matrix metalloproteinases (MMPs), thereby inhibiting the action of MMPs, inducing extracellular matrix degradation, and inhibiting angiogenesis, tumor growth and invasion, and metastasis.
This agent may also inhibit tumor necrosis factor-alpha converting enzyme (TACE), an enzyme involved in tumor necrosis factor alpha (TNF-alpha) production that may play a role in some malignancies as well as in the development of arthritis and sepsis.

32. 2- PRINOMASTAT
A synthetic hydroxamic acid derivative with potential antineoplastic activity.
Prinomastat inhibits matrix metalloproteinases (MMPs) (specifically, MMP-2, 9, 13, and 14), thereby inducing extracellular matrix degradation, and inhibiting angiogenesis, tumor growth and invasion, and metastasis.
As a lipophilic agent, prinomastat crosses the blood-brain barrier.

33. Miscellaneous Biological and Targeted Therapy

34. Nanogold
Many cancer cells have a protein, known as epidermal growth factor receptor (EGFR), all over their surface, while healthy cells typically do not express the protein as strongly. By conjugating, or binding, the gold nanoparticles to an antibody for EGFR, suitably named anti-EGFR, the researchers were able to get the nanoparticles to specifically attach themselves to the cancer cells.
Now we have examined how the particles’ ability to absorb light helps kill those cancer cells

35. cancer vaccines
Cancer vaccines are medicines that belong to a class of substances known as biological response modifiers. Biological response modifiers work by stimulating or restoring the immune system’s ability to fight infections and disease. There are two broad types of cancer vaccines:
Preventive (or prophylactic) vaccines, which are intended to prevent cancer from developing in healthy people; and
Treatment (or therapeutic) vaccines, which are intended to treat an existing cancer by strengthening the body’s natural defenses against the cancer .

36. Cancer preventive vaccines target infectious agents that cause or contribute to the development of cancer.
cancer preventive vaccines are based on antigens that are carried by infectious agents and that are relatively easy for the immune system to recognize as foreign.
the U.S. Food and Drug Administration (FDA) has approved two vaccines, Gardasil® and Cervarix®, that protect against infection by the two types of HPV—types 16 and 18—that cause approximately 70% of all cases of cervical cancer worldwide. HPV types 16 and/or 18 also cause some vaginal, vulvar, anal, penile, and oropharyngeal cancers

37. Cancer treatment vaccines are designed to treat cancers that have already developed.
They are intended to delay or stop cancer cell growth; to cause tumor shrinkage; to prevent cancer from coming back; or to eliminate cancer cells that have not been killed by other forms of treatment.
The FDA approved the first cancer treatment vaccine. This vaccine, (Provenge®), is approved for use in some men with metastatic prostate cancer.
It is designed to stimulate an immune response to prostatic acid phosphatase (PAP), an antigen that is found on most prostate cancer cells.
In a clinical trial, it increased the survival of men with a certain type of metastatic prostate cancer by about 4 months

38. Researchers are studying several ways to treat cancer using gene therapy.
Some approaches target healthy cells to enhance their ability to fight cancer.
Other approaches target cancer cells, to destroy them or prevent their growth.
Some gene therapy techniques under study are described below.
In one approach, researchers replace missing or altered genes with healthy genes (e.g., p53).
Scientists are investigating the insertion of genes into cancer cells to make them more sensitive to chemotherapy, radiation therapy, or other treatments.

39. In other studies, researchers remove healthy blood- forming stem cells from the body, insert a gene that makes these cells more resistant to the side effects of high doses of anticancer drugs, and then inject the cells back into the patient.
In another approach, researchers introduce “suicide genes” into a patient's cancer cells. A pro-drug (an inactive form of a toxic drug) is then given to the patient. The pro-drug is activated in cancer cells containing these “suicide genes, ” which leads to the destruction of those cancer cells.
Other research is focused on the use of gene therapy to prevent cancer cells from developing new blood vessels (angiogenesis).