Antibody-Based Cancer Drugs

 

The immune system in human body consists of cells that generate effective factors defending the body against pathogens (antigens). Antibody produced by B lymphocyte is an important arm of the defense mechanism. Cancer cells have cancer-associated antigens on the surface. The antibody attaches to the antigens on the surface of cancer cells. The cancer cells can thus be identified and destroyed by antibodies or other cells in the immune system.

 

Hybridoma technology makes mass-production of antibody possible. It is achieved by fusing a myeloma (a type of bone marrow cancer) with B cell that produces a specific antibody. Thus, the combination of a B cell that can recognize a particular antigen and a myeloma cell that lives indefinitely makes the hybridoma cell a kind of perpetual antibody-generating machine. Since the antibodies are all identical clones produced from a single (mono) hybridoma cell, they are called monoclonal antibodies (Mabs).

 

Antibody-based cancer therapy have enjoyed a renaissance. Since the first Mab, Rituxan, was approved for patients with non-Hodgkin's lymphoma in November 1997, there are currently eight Mabs available for treatment of different kind of cancers (Table 1.1). The applications of these Mab for treatment of cancer patient will likely generate significant excitement and growing acceptance by the medical community, which led to a high level of regulatory comfort. In future, the number of Mabs that will be approved is likely going to be much higher taking into account that there are huge numbers of antibodies in clinical development (Table 1).

 

Table 1. T Cell-Based Cancer Drugs

 

Product	Target	Indication	Clinical status	Manufacturer
Avastin (Bevacizumab)	Vascular endothelial growth factor	Colorectal cancer	Market	Genentech
Bexxar (Iodine 131 Tositumomab)	CD20	B-cell non-Hodgkin's lymphoma	Market	GlaxoSmithKline (Corixa)
Campath (Alemtuzumab)	CD52	B cell chronic lymphocytic leukemia	Market	Genzyme and Millennium
Erbitux (Cetuximab)	Epidermal growth factor receptor	Colorectal cancer	Market	Bristol-Myers Squibb and ImClone
Herceptin (Trastuzumab)	HER2	Breast cancer	Market	Genentech
Mylotarg (Gemtuzumab ozogamicin)	CD33	Acute myeloid leukemia	Market	UCB (Celltech) and Wyeth
Rituxan (Rituximab)	CD20	B-cell non-Hodgkin's lymphoma	Market	BiogenIdec and Genentech
Vectibix (ABX-EGF,  (Panitumumab)	Epidermal growth factor receptor	Metastatic Colorectal cancer	Market	Amgen (Abgenix)
Zevalin (Yttrium-90, Ibritumomab tiuxetan)	CD20	B-cell non-Hodgkin's lymphomas	Market	BiogenIdec
Vectibix (ABX-EGF,  (Panitumumab)	Epidermal growth factor receptor	Esophageal, kidney, lung, and pancreatic cancers	Phase III	Amgen (Abgenix)
ABX-MA1	MUC18	Melanoma	Phase I	Amgen (Abgenix
Avastin alone or + Tarceva		Liver cancer	Phase II	Genentech
CDP791	Vascular endothelial growth factor	Non-small cell lung cancer	Phase II	UCB (Celltech)
CDP860	Beta receptor of platelet growth factor	Various tumors	Phase II	UCB (Celltech)
CMC544	Antibdoy-cytotoxic conjugate	Non-Hodgkin's Lymphoma	Phase I	UCB (Celltech)
Cotara	Tumor necrosis factor	Brain tumor	Phase II	Peregrine
DenosuMab (AMG162)	Receptor activator of nuclear factor kappa B ligand	Advanced breast cancer with bone metastasis	Phase II	Amgen
HuC242-DM4	CanAg	Various tumor	Phase I	ImmunoGen
HuN901-DM1	CD56	Small cell lung cancer and multiple myeloma	Phase I/II	ImmunoGen
IMC-BEC2	GD3	Lung cancer	Phase III	ImClone
IMC-1121b	Vascular endothelial growth factor	Colorectal cancer	Phase I	ImClone
IMC-11F8	Epidermal growth factor receptor	Solid and liquid tumors	Phase I	ImClone
Lymphocide (Eparatuzumab, Immu103)	CD22 in B cells	Non-Hodgkin's lymphoma	Phase II	Immunomedics
MDX-010 (Ipilimumab)	Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)	Breast cancer, melanoma, and prostate cancer	Phase II/III	Medarex
MDX-060	CD30	Hodgkin's disease and anaplastic large cell lymphoma	Phase II	Medarex
MDX-070	Prostate-specific membrane antigen (PSMA)	Prostate cancer	Phase II	Medarex
MDX-214	Epidermal growth factor receptor	EGFR-positive cancers	Phase I	Medarex
MLN2704	PSMA targeting Mab with a chemothera- peutic agent	Prostate cancer	Phase 1	Millennium
Omnitarg	HER	Breast, lung, prostate, and ovarian cancers	Phase II	Genentech
SGN-30	CD30	Hodgkin's disease	Phase II	Seattle Genetics
SGN-40	CD40	Multiple myeloma	Phase I	Seattle Genetics
Vitaxin	Integrins	Melanoma and prostate cancer	Phase II	MedImmune
Ticilimumab (CP-675206)	CTLA-4	Melanoma	Phasee III	Pfizer (Abgenix)

 

 

There are two major types of Mabs used in cancer therapy. One is Mab alone. Mabs attach themselves to specific antigens on cancer cells. The interaction between Mab and cell surface molecules results in anti-cancer effects. The other is conjugated Mab. This is to connect radioactive moieties, toxins, enzymes, or prodrugs to a Mab. The conjugated Mab has the capacity to recognize and attach to cancer cells, which bring the attached drugs to kill the targeted cancer cells.

 

CD20 is a B-cell-specific protein. Rituxan is used for treatment of B-cell non-Hodgkin's lymphoma. This drug binds to CD20 on the surface of lymphoma cells, targeting them for destruction through several possible mechanisms, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. CD52 is an important marker for B cell chronic lymphocytic leukemia on cell surface. Campath binds to CD52 and from there, it recruits the body's immune system to attack and kill the marked leukemia cells.

 

Epidermal growth factor receptor (EGFR) normally helps regulate the growth of many different cells in the body. EGFR also can stimulate cancer cells to grow. Many cancer cells require signals mediated by EGFR for their survival. Residing on the surface of these tumor cells, EGFR is activated when naturally occurring proteins in the body, such as epidermal growth factor (EGF) or transforming growth factor alpha (TGF-α), bind to it. This binding changes the shape of EGFR, which, in turn, triggers internal cellular signals that stimulate tumor cell growth. Erbitux and Panitumumab binds to EGFR, preventing the natural ligands such as EGF and TGF-α from binding to the receptor and interfering with the signals that would otherwise stimulate growth of the cancer cells. This blockade also interferes with tumor invasion and metastases, cell division, and angiogenesis. IMC-11F8 is a fully human monoclonal antibody that is designed to bind to the EGFR, thereby inhibiting certain ligands known as growth factors from binding to and activating the receptor. This action blocks a signal pathway key to tumor growth and repair and has also been shown to induce cell death, or apoptosis, in human tumors.

 

Heceptin attaches to human epidermal growth factor receptor 2 (HER2) and blocks the other molecules from binding there. This Mab thus prevents the cancer cells from growing rapidly. Omnitarg is a humanized antibody and the first in a new class of agents known as HER dimerization inhibitors (HDIs). HDIs block the ability of the HER2 receptor to collaborate with other HER receptor family members (HER1/EGFR, HER3, and HER4). In cancer cells, interfering with HER2's ability to collaborate with other HER family receptors blocks cell signaling and may ultimately lead to cancer cell growth inhibition and death of the cancer cell. HDIs, because of their unique mode of action, have the potential to work in a wide variety of tumors, including those that do not overexpress HER2.

 

Formation of new blood vessels is critical for tumor growth. The growth of the endothelial cells that form the inner lining of the blood vessels is one of the most important step in establishing new blood vessels. Vascular endothelial growth factor (VEGF) makes a significant contribution to this process.Avastin binds to VEGF, inhibits VEGF, and prevents tumor angiogenesis (the formation of new blood vessels). CDP791 was also designed to target vascular endothelial growth factor to interrupt the growth of the blood vessels. IMC-1121B is a fully human monoclonal antibody that is designed to bind to the VEGFR-2 found on tumor vasculature, thereby inhibiting vascular endothelial growth factors from binding to and activating the receptor.

 

During angiogenesis, proteins called integrins are expressed on the surface of these new vessels, which enable the integrins to adhere to the surrounding tissue, allowing them to continue their extension toward and into the tumor. Vitaxin has been shown to bind and block alpha-v beta-3, an integrin which is specifically found on these newly sprouting blood vessels, and to stop the growth of these vessels through an apoptotic (programmed cell death) signaling mechanism.

 

Denosumab is a fully human monoclonal antibody that specifically targets the receptor activator of nuclear factor kappa B ligand (RANKL), a key mediator of the resorptive phase of bone remodeling. Denosumab is being studied across a range of conditions, including cancer bone metastases and multiple myeloma.

 

The conjugated-antibody delivers radioactive moieties, toxins, enzymes, or prodrugs directly to the cancer cells. The conjugated Mab circulates in the body and attach to a cancer cell with a matching antigen. It directs the therapeutic agents to the targeted cells and minimizes damage to the normal cells.

 

Zevalin is the first radiolabeled Mab approved for treatment of cancer. It delivers radioactivity to cancerous B lymphocytes and is used to treat B cell non-Hodgkin's lymphoma. Another radiolabeled Mab, Bexxar, is also used to treat B cell non-Hodgkin's lymphoma.

 

Mylotarg is a Mab conjugated with a toxin called calicheamicin. The antibody targets the CD33 antigen, which is present on most leukemia cells. It is used to treat acute myelogenous leukemia.

 

MLN2704 consists of a targeting monoclonal antibody vehicle designed to deliver a lethal payload specifically to tumor cells that express prostate-specific membrane antigen (PSMA) on their surfaces. The lethal payload consists of the chemotherapeutic agent maytansinoid (DM1). PSMA is expressed on virtually all prostate cancer cells, both primary and metastatic, and its abundance on the cell surface increases as the cancer progresses. Thus MLN2704 recognizes, attaches, and delivers drug to kill tumor cells.

 

HuN901-DM1 comprises huN901 antibody, which targets CD56, and DM1 cell-killing agent, a tumor activated prodrug (TAP). A TAP compound consists of: a monoclonal antibody that binds specifically to a target – its antigen – found on cancer cells with a potent cell-killing agent attached. The antibody serves to target the compound specifically to cancer cells and the cell-killing agent serves to kill the cancer cells. HuC242-DM4 comprises huC242 CanAg-targeting antibody and DM4 cell-killing agent

 

Cotara is an antibody conjugated to Iodine 131, a therapeutic radioisotope. The antibody is specific for tumor necrosis factor, which is concentrated in the core of the tumor. Thus it is attracted to necrotic regions throughout the tumor, the radioisotope can be delivered to neighboring viable cancer cells, resulting in their death.

 

ABX-MA1 targets a protein called MUC18, a cell surface adhesion molecule that is highly expressed on metastatic melanoma cells but not on normal skin cells. MUC18 has been demonstrated to play a critical rolel in melanoma growth and metastasis by regulating the adhesion and interaction between melanoma cells and surrounding skin cells and new blood vessel cells. Binding of the MUC18 antigen by ABX-MA1 inhibited primary melanoma tumor growth and the formation of tumor metastases.

 

Anti-idiotype antibody technology can be used to generate anti-tumor activities. The variable regions in the antibody bear unique antigenic determinants called idiotopes. Anti-idiotypic (anti-id) antibodies can potentially induce a human anti-anti-idiotypic response. The anti-anti-idiotypic antibodies mimic the original antigen. Because of this mimicry, vaccination with anti-id has induced protective immunity. However, very limited success was achieved in this field. IMC-BEC2 is an investigational anti-idiotypic monoclonal antibody that mimics GD3, a ganglioside expressed on the cell membrane of most small cell lung cancer tumors. It failed in Phase III clinical trial.

 

Humanized antibodies represent an enormous leap forward among potentially effective anticancer treatments. It is feasible for the antibody to maintain the capacity of recognizing the antigen and to have structure like a human antibody. This is done by the transfer of the murine CDRs (complementary determining regions) to a human framework. Most of the antibodies listed in the Tables 1 are humanized antibodies.

 

The genomics/proteomics revolution that is currently taking place will provide an exploding number of genetic and biological targets over the next several years. Antibodies are becoming a very important and attractive class of drugs and cheapest way to transfer discoveries in genomics/proteomics into globally marketable novel drugs. The preclinical development pathways for antibodies are now well-known, and antibodies can typically be developed in a much shorter length time than small molecules. This ability to shorten the time to market and thus, development costs, will make antibodies increasing valuable as new disease targets proliferate over the next decades to come.