Immunotherapy:Targeted Antibodies “Naked” mAbs, ADCs, BiTEs, and More Targeted Antibodies Treatment Options CRI's Impact Clinical Trials Targeted Antibodies: Monoclonal Antibodies, Antibody-Drug Conjugates, and Bispecific Antibodies Reviewed by: Rony Dahan, PhDWeizmann Institute of Science 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. 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. “Naked” Monoclonal Antibodies (mAbs) Antibody-Drug Conjugates (ADCs) Bispecific Antibodies Most targeted antibodies are referred to as “passive” immunotherapies because they target tumor cells directly rather than immune cells; however, more recent innovations have produced variations of targeted antibodies that are considered “active” immunotherapies because they target immune cells, too. (See bispecific antibodies below for more on these.) 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. “Naked” Monoclonal Antibodies (mAbs) 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 (direct killing by the “front” end). These antibodies can also signal to other immune cells to eliminate the cancer cells (immune-mediated killing by the “back” end). In 1997, the U.S. Food and Drug Administration (FDA) approved the first antibody for the treatment of cancer—the monoclonal antibody rituximab (Rituxan®) 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. By delivering these chemotherapeutic drugs directly to tumors, it can potentially reduce the side effects associated with indiscriminate deployment of these toxic components. 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 to create a product that can bind to two different targets. Some bispecific antibodies, known as bispecific T cell engagers, or BiTEs, target both cancer cells and immune cells known as T cells. These BiTEs work to bring T cells into close proximity with—and enable them to eliminate—cancer cells. Due to their ability to target immune cells directly, these BiTEs are considered “active” immunotherapies. The first bispecific antibody—a BiTE called blinatumomab (Blincyto®)—was approved by the FDA in 2014 for subsets of patients with leukemia. Other bispecific antibodies have been developed to target different cancer antigens. Targeted Antibody Treatment Options There are several 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, liver 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 Isatuximab (Sarclisa®): a monoclonal antibody that targets the CD38 pathway; approved for subsets of patients with multiple myeloma Margetuximab-cmkb (Margenza™): a monoclonal antibody that targets the HER2 pathway; approved in combination with chemotherapy for subsets of patients with advanced breast cancer Mogamulizumab (Poteligeo®): a monoclonal antibody that targets the CCR4 pathway; approved for subsets of patients with two rare types of non-Hodgkin lymphoma, mycosis fungoides and Sézary syndrome Naxitamab-gqgk (Danyelza®): a monoclonal antibody that targets the GD-2 pathway; approved for subsets of patients with neuroblastoma 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, liver 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 Tafasitamab (Monjuvi®): a monoclonal antibody that targets the CD19 pathway; approved for subsets of patients with 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 Enfortumab vedotin (Padcev™): an antibody-drug conjugate that targets the Nectin-4 pathway and delivers toxic drugs to tumors; approved for subsets of patients with advanced bladder cancer 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 Loncastuximab tesirine (Zynlonta™): an antibody-drug conjugate that targets the CD19 pathway and delivers toxic drugs to tumors; approved for subsets of patients with lymphoma Mirvetuximab soravtansine (ElahereTM): an antibody-drug conjugate that targets the folate receptor apathway and delivers toxic drugs to tumors; approved for subsets of patients with advanced ovarian cancer 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 Polatuzumab vedotin (Polivy™): an antibody-drug conjugate that targets the CD79b pathway and delivers toxic drugs to tumors; approved for subsets of patients with lymphoma Sacituzumab govitecan-hziy (Trodelvy™): an antibody-drug conjugate that targets the TROP-2 pathway; approved for subsets of patients with breast cancer Tisotumab vedotin (Tivdak™): an antibody-drug conjugate that targets tissue factor (TF); approved for subsets of patients with advanced cervical cancer Trastuzumab deruxtecan (Enhertu®): an antibody-drug conjugate that targets the HER2 pathway and delivers toxic drugs to tumors; approved for subsets of patients with breast cancer, esophageal cancer, lung cancer, and stomach cancer 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 Amivantamab (Rybrevant™): a bispecific antibody that targets EGFR and MET receptors on tumor cells; approved for subsets of patients with lung cancer 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 Epcoritamab (EpkinlyTM): a bispecific antibody that targets CD20 on tumor cells as well as CD3 on T cells; approved for subsets of patients with relapse or refractory B cell lymphomas Glofitamab (ColumviTM): a bispecific antibody that targets CD20 on tumor cells as well as CD3 on T cells; approved for subsets of patients with relapse or refractory B cell lymphomas Mosunetuzumab (LunsumioTM): a bispecific antibody that targets CD20 on lymphoma cells and CD3 on T cells; approved for subsets of patients with relapsed or refractory follicular lymphoma Tebentafusp-tebn (Kimmtrak®): a bispecific antibody that targets the gp100 protein on tumor cells and CD3 on T cells; approved for subsets of patients with melanoma Teclistimab (TecvayliTM): a bispecific antibody that targets BCMA on tumor cells as well as CD3 on T cells; approved for subsets of patients with multiple myeloma Side Effects Potential side effects may vary according to the type of targeted antibody—and what exactly it targets—and may 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 may sometimes cause off-target immune responses that result in side effects. These potential side effects can range from mild to moderate and can become life-threatening 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. Common side effects associated with targeted antibodies may include but are not limited to: 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. 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. CRI has also funded 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, MD, CRI’s founding scientific and medical director, CRI postdoctoral fellow Hiroshi Shiku, MD, and CRI grantee Herbert Oettgen, MD—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 Laureate Susumu Tonegawa, PhD, of the Massachusetts Institute of Technology, 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, MD, of the Fred Hutchinson Cancer Research Center, led the clinical studies that resulted in the first FDA approval of an antibody-drug conjugate, in 2000, for acute myeloid leukemia. In 2000, CRI investigator Raphael Clynes, PhD, CRI postdoctoral fellow Terri Towers, PhD, and Jeffrey Ravtech, MD, PhD, 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, DPhil, 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, MD, PhD, and Rakesh Jain, PhD, showed that a VEGF-blocking antibody blocked tumor blood vessel growth in human rectal cancer. Currently, CRI is funding several grantees whose research involves targeted antibodies and is currently funding a phase 2 clinical 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, MD, of the Dana-Farber Cancer Institute. 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 Claudin 18.2: a surface protein overexpressed in some esophageal cancers and involved in invasion and survival DKK1: a secreted protein involved in migration, self-renewal, and 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. Find an Immunotherapy Clinical Trial Create a profile and fill out a questionnaire to identify immunotherapy clinical trials for which you may be eligible. Need more information? Learn more about clinical trials. Find a Clinical Trial News & Events AACR 2022 Recap: T Cells Still On Top, But Make Room for Myeloid Cells At the 2022 AACR annual meeting, CRI scientists highlighted a wide scope of cancer immunology advances, and brought myeloid… #Immune2Cancer Day 2022 On Friday, June 10, 2022, we invite you to raise awareness of the lifesaving potential of immunotherapy. Giving Tuesday 2022 Be a part of the global generosity movement and celebrate all acts of giving. #GivingTuesday
AACR 2022 Recap: T Cells Still On Top, But Make Room for Myeloid Cells At the 2022 AACR annual meeting, CRI scientists highlighted a wide scope of cancer immunology advances, and brought myeloid…
#Immune2Cancer Day 2022 On Friday, June 10, 2022, we invite you to raise awareness of the lifesaving potential of immunotherapy.
Giving Tuesday 2022 Be a part of the global generosity movement and celebrate all acts of giving. #GivingTuesday