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  • Targeted Antibodies
  • Treatment Options
  • CRI's Impact
  • Clinical Trials

Monoclonal Antibodies, Antibody-Drug Conjugates, and Bispecific Antibodies

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Targeted antibodies are a form of cancer immunotherapy treatment that can disrupt cancer cell activity and alert the immune system to target and eliminate cancer cells.

Antibodies are proteins that are naturally produced by a type of immune cell called B cells and serve to protect us against a variety of threats, such as bacteria, viruses, and cancer cells. Antibodies do this by precisely targeting and binding to cell surface markers known as antigens. Once antibodies bind to cancer cells, they can disrupt pathways that are important to cancer cell activity, like those that allow them to grow uncontrollably. These antibodies can also signal to other immune cells to eliminate the cancer cells.

  • Monoclonal Antibodies (mAbs)
  • Antibody-Drug Conjugates (ADCs)
  • Bispecific Antibodies

Due to their cancer-targeting properties, many different targeted antibodies are currently being evaluated, both alone and in combination with other treatments, in a variety of cancer types in clinical trials.

Monoclonal Antibodies (mAbs)

On its own, our immune system has the ability to make trillions of different types of antibodies. Now, scientists can supplement our immune system by creating and customizing antibodies against specific cancer targets in the lab. These are often referred to as monoclonal antibodies due to their identical structure.

In 1997, the U.S. Food and Drug Administration (FDA) approved the first antibody for the treatment of cancer—the monoclonal antibody rituximab for leukemia—and since then, over a dozen more have received FDA approval.

Antibody-Drug Conjugates (ADCs)

More recently, advances in technology have enabled the development of new antibody-based immunotherapies. One such approach is antibody-drug conjugates (ADCs), in which a targeted antibody is equipped with anti-cancer drugs, so that when the antibody targets and binds to cancer cells, it also delivers a toxic drug that can kill the cancer cells.

Bispecific Antibodies

Another new type of antibody-based immunotherapy that has been developed is bispecific antibodies. These are made by taking the targeting front end regions of two different antibodies and combining them together to create a product that can bind to two different targets. The first bispecific antibody—blinatumomab—was approved by the FDA in 2014 for subsets of patients with leukemia. Blinatumomab is known as a bispecific T cell engager (BiTE) because it is designed to bind cancer cells as well as T cells. As a result, blinatumomab can bring T cells into close proximity with—and enable them to eliminate—cancer cells. Other bispecific antibodies have been developed to target different cancer antigens.

Targeted Antibody Treatment Options

There are currently 22 targeted antibody-based immunotherapies that have been approved by the FDA for the treatment of cancer:

Monoclonal Antibodies

  • Alemtuzumab (Campath®): a monoclonal antibody that targets the CD52 pathway; approved for subsets of patients with leukemia
  • Bevacizumab (Avastin®): a monoclonal antibody that targets the VEGF/VEGFR pathway and inhibits tumor blood vessel growth; approved for subsets of patients with brain cancer, cervical cancer, colorectal cancer, kidney cancer, lung cancer, and ovarian cancer
  • Cetuximab (Erbitux®): a monoclonal antibody that targets the EGFR pathway; approved for subsets of patients with colorectal cancer, and head and neck cancer
  • Daratumumab (Darzalex®): a monoclonal antibody that targets the CD38 pathway; approved for subsets of patients with multiple myeloma
  • Denosumab (Xgeva®): a monoclonal antibody that targets the RANKL pathway; approved for subsets of patients with sarcoma
  • Dinutuximab (Unituxin®): a monoclonal antibody that targets the GD2 pathway; approved for subsets of patients with pediatric neuroblastoma
  • Elotuzumab (Empliciti®): a monoclonal antibody that targets the SLAMF7 pathway; approved for subsets of patients with multiple myeloma
  • Necitumumab (Portrazza®): a monoclonal antibody that targets the EGFR pathway; approved for subsets of patients with lung cancer
  • Obinutuzumab (Gazyva®): a monoclonal antibody that targets the CD20 pathway; approved for subsets of patients with leukemia and lymphoma
  • Ofatumumab (Arzerra®): a monoclonal antibody that targets the CD20 pathway; approved for subsets of patients with leukemia
  • Olaratumumab (Lartruvo®): a monoclonal antibody that targets the PDGFRα pathway; approved for subsets of patients with sarcoma
  • Panitumumab (Vectibix®): a monoclonal antibody that targets the EGFR pathway; approved for subsets of patients with colorectal cancer
  • Pertuzumab (Perjeta®): a monoclonal antibody that targets the HER2 pathway; approved for subsets of patients with breast cancer
  • Ramucirumab (Cyramza®): a monoclonal antibody that targets the VEGF/VEGFR2 pathway and inhibits tumor blood vessel growth; approved for subsets of patients with colorectal cancer, esophageal cancer, lung cancer, and stomach cancer
  • Rituximab (Rituxan®): a monoclonal antibody that targets the CD20 pathway; approved for subsets of patients with leukemia and lymphoma
  • Trastuzumab (Herceptin®): a monoclonal antibody that targets the HER2 pathway; approved for subsets of patients with breast cancer, esophageal cancer, and stomach cancer

Antibody-Drug Conjugates

  • Brentuximab vedotin (Adcetris®): an antibody-drug conjugate that targets the CD30 pathway and delivers toxic drugs to tumors; approved for subsets of patients with lymphoma
  • Gemtuzumab ozogamicin (MyloTarg®): an antibody-drug conjugate that targets the CD33 pathway and delivers toxic drugs to tumors; approved for subsets of patients with leukemia
  • Ibritumomab tiuxetan (Zevalin®): an antibody-drug conjugate that targets the CD20 pathway and delivers toxic drugs to tumors; approved for subsets of patients with lymphoma
  • Inotuzumab ozogamicin (Besponsa®): an antibody-drug conjugate that targets the CD22 pathway and delivers toxic drugs to tumors; approved for subsets of patients with leukemia
  • Moxetumomab pasudotox (Lumoxiti®): an antibody-drug conjugate that targets the CD22 pathway and delivers toxic drugs to tumors; approved for subsets of patients with leukemia
  • Trastuzumab emtansine (Kadcyla®): an antibody-drug conjugate that targets the HER2 pathway and delivers toxic drugs to tumors; approved for subsets of patients with breast cancer

Bispecific Antibodies

  • Blinatumomab (Blincyto®): a bispecific antibody that targets CD19 on tumor cells as well as CD3 on T cells; approved for subsets of patients with leukemia

Side Effects

Side effects can vary according to the type of targeted antibody—and what exactly it targets—and can also be influenced by the location and type of cancer as well as a patient’s overall health. As many of the proteins targeted by antibodies are expressed by both cancer cells and healthy cells, targeted antibodies can sometimes cause off-target immune responses that result in side effects.

These side effects can range from mild to moderate and can become deadly under certain circumstances. Fortunately, in most cases side effects can be safely managed as long as they are recognized and addressed early. Therefore, it’s extremely important that patients notify their care team as soon as possible about any unusual developments during or after treatment with immunotherapy. In addition, patients should always consult their doctors and the rest of their care team to gain a better and fuller understanding of the potential risks and side effects associated with specific targeted antibodies.

The side effects most commonly associated with currently approved targeted antibodies are: anemia, constipation, cough, decreased appetite, diarrhea, fatigue / asthenia, fever, headache, hemorrhage, hypokalemia, infection, infusion-related reactions, lymphopenia, nasopharyngitis, nausea, neutropenia, pain (including in the abdomen, back and musculoskeletal system), peripheral neuropathy, pneumonia, pruritus, pyrexia, rash, thrombocytopenia, and vomiting.

For more information regarding the side effects associated with targeted antibodies and other immunotherapy approaches, please refer to our Immunotherapy Side Effects page.

CRI's Impact in Targeted Antibodies

Throughout its history, the Cancer Research Institute has supported a variety of basic research aimed at improving our understanding of antibodies as well as translational and clinical efforts that seek to use these insights in the development of antibody-based therapies for the treatment of cancer patients in the clinic:

  • In the 1970s, Lloyd J. Old, M.D., CRI’s founding scientific and medical director, CRI postdoctoral fellow Hiroshi Shiku, M.D., and CRI grantee Herbert Oettgen, M.D.—all of Memorial Sloan Kettering Cancer Center—found cancer-targeting antibodies in the blood of both melanoma and kidney cancer patients, thus providing evidence of the existence of natural immune responses against cancer.
  • In 1983, Nobel Prize winner Susumu Tonegawa, Ph.D., of the Massachusetts Institute of Technology (MIT), with funding from CRI, discovered how the immune system can create trillions of customized antibodies.
  • In the late 1990s, former CRI postdoctoral fellow Irwin Bernstein, M.D., of the Fred Hutchinson Cancer Research Center, led the clinical studies that resulted in the approval of the first FDA-approved antibody-drug conjugate, in 2000 for acute myeloid leukemia.
  • In 2000, CRI investigator Raphael Clynes, Ph.D., CRI postdoctoral fellow Terri Towers, Ph.D., and Jeffrey Ravtech, M.D., Ph.D., all of The Rockefeller University, revealed that the antitumor activity of targeted antibodies depends upon the binding and activation of their “back ends.”
  • In 2000-2001, CRI grantee Malcolm A. S. Moore, D.Phil., of Memorial Sloan Kettering Cancer Center, revealed that the VEGF/VEGF-R2 pathway can activate leukemia cell growth and migration, and that inhibition of this pathway is essential for long-term leukemia remission. In 2009, CRI postdoctoral fellow Gabriel Duda, M.D., Ph.D., and Rakesh Jain, Ph.D., showed that a VEGF-blocking antibody blocked tumor blood vessel growth in human rectal cancer.

Currently, CRI is funding the following grantees whose research involves targeted antibodies:

  • Lily Wang, Ph.D.—a CRI CLIP Investigator at the Medical College of Wisconsin—is exploring the therapeutic potential of a new cancer immunotherapy target that she recently discovered on T cells that also appears to be a prognostic marker for breast cancer.
  • Andrew I. Flyak, Ph.D.—a CRI postdoctoral fellow at the California Institute of Technology—is analyzing the antibodies in patients whose immune systems naturally eliminated hepatitis C viral infections in order to potentially reverse engineer them to treat other patients.
  • Haiqiang Dai, Ph.D., <<HYPERLINK TO COME>>—a CRI postdoctoral fellow at in the Boston Children’s Hospital lab of Frederick W. Alt, Ph.D.—is investigating the mechanisms behind the development of antibody repertoires in order to help advance new approaches to generate therapeutic antibodies for treatment.

Additionally, CRI is currently funding the following clinical trial involving targeted antibody therapy:

  • A phase II trial (NCT02336165) combining a targeted antibody, a checkpoint inhibitor, and radiation therapy in patients with glioblastoma, an aggressive form of brain cancer. This trial is being led by David A. Reardon, M.D., of the Dana-Farber Cancer Institute.
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Targeted Antibody Clinical Trial Targets

Antibody targets under evaluation in clinical trials include:

  • Angiopoietin: a protein that can promote blood vessel formation in tumors
  • BCMA: an important signaling receptor found mainly on mature B cells; often expressed by lymphoma and myeloma cells
  • CD19: a receptor found on the surface of almost all B cells that influences their growth, development, and activity; often expressed by leukemia, lymphoma, and myeloma cells
  • CD20: a receptor found on the surface of B cells during their development; often expressed by leukemia, lymphoma, and myeloma cells
  • CD22: a receptor found primarily on the surface of mature B cells; often expressed by leukemia and lymphoma cells
  • CD25 (also known as IL2-R): a cytokine receptor involved in the growth and expansion of immune cells; often expressed by leukemia and lymphoma cells
  • CD30: a receptor that is expressed on certain types of activated immune cells; often expressed by leukemia and lymphoma cells
  • CD33: a surface receptor found on several types of immune cells; often expressed by leukemia cells
  • CD37: a protein found on many types of immune cells; often expressed by leukemia and lymphoma cells
  • CD38: an immune cell surface protein that plays roles in cell adhesion and signaling; often expressed by leukemia and myeloma cells
  • CD52: a protein found on the surface of mature immune cells as well as other cell types
  • CD56: a protein found on both neurons and natural killer immune cells
  • CD123 (also known as IL-3R): a receptor found on immune cells that is involved in cellular proliferation and differentiation and is often expressed by leukemia and lymphoma cells
  • cMET: a growth-related pathway that is often abnormally activated in cancer
  • DLL/Notch: a pathway that can promote cell growth
  • EGFR: a pathway that controls cell growth and is often mutated in cancer
  • EpCAM: a pathway that controls cell growth and adhesion
  • FGF/FGF-R: a pathway that controls cell growth, death, and migration
  • GD2: a pathway that controls cell growth, adhesion, and migration, and is often abnormally overexpressed in cancer cells
  • HER2: a pathway that controls cell growth and is commonly overexpressed in cancer and associated with metastasis
  • Mesothelin: a protein that is commonly overexpressed in breast cancer and may aid metastasis
  • Nectin-4: a pathway that controls cell growth and adhesion
  • PDGFRα: a surface receptor that plays a role in stimulating cell division and growth
  • RANKL: a protein that plays a role in bone regeneration and modeling, and is often overexpressed in cancer
  • SLAMF7: a surface protein found on plasma B cells; often expressed by lymphoma and myeloma cells
  • TROP2: a protein that is commonly overexpressed in cancer and appears to aid cancer cell self-renewal, proliferation, invasion, and survival
  • VEGF/VEGF-R: a pathway that, when targeted with treatment, can prevent tumor blood vessel formation

In addition to these antibody targets currently being evaluated in clinical trials, new targets and approaches are constantly being developed and investigated in clinical trials. To determine if you or someone you know might be eligible for an immunotherapy clinical trial, please consult our Clinical Trial Finder service.

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Sources: CRI documents; U.S. Food and Drug Administration (FDA); FDA Hematology/Oncology (Cancer) Approvals & Safety Notifications; FDA Online Label Repository

Updated April 2019

*Immunotherapy results may vary from patient to patient. Consult a health care professional about your treatment options.

*Immunotherapy results may vary from patient to patient.

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