Over the past decade, therapeutic antibodies such as Rituxan (rituximab) from Genentech/Biogen Idec,and Genentech’s Avastin (bevacizumab) have played a significant role in cancer treatment. Combined with chemotherapy, they are becoming standard treatment for certain cancers. Despite these advances, however, there remains significant unmet need in cancer treatment. This unmet need, coupled with the commercial attractiveness of the oncology market, has led to pharma investing a significant portion of its R&D budget in the development of new approaches to antibodies for cancer. As biosimilar approaches to Ritxuan, Herceptin (trastuzumab) from Genentech, and Erbitux (cetuximab), from Bristol-Meyers Squibb, ImClone and Merck Serono are likely to become available in the next few years, new drugs will need to show more dramatic improvements in safety and efficacy if they are to become successful.
Companies are pursuing three types of enhancements to antibodies in search of improved product profiles. These enhancements include tuned, conjugated and bi-specifics.
Tuned antibodies are engineered to better engage the immune system’s natural killer cells to target and attack cancer cells. A recent example of a tuned antibody in development is GA101 from Glycart and Roche. GA101 is a humanized anti-CD20 monoclonal antibody engineered to increase target cell death. Phase 1 data presented at the American Society of Hematology meeting in 2008 showed that GA101 produced a 58% overall response rate in relapsed/refractory NHL patients.1
Conjugated antibodies contain cancer-killing agents, such as chemotherapy, toxins, or radioisotopes. Conjugated antibodies, however, have experienced limited success as a result of toxicity issues and complicated methods of administration. Examples of conjugated antibodies include the radioimmunotherapies Bexxar (Tositumomab) from GlaxoSmithKline and Zevalin (ibritumomab tiuxetan) from Spectrum Pharmaceuticals; and Wyeth’s drug-conjugated antibody Mylotarg (Gemtuzumab ozogamicin). More recent approaches in development appear to largely avoid these unwanted side-effects.
Bi-specific antibodies utilize the body’s own immune system, specifically T cells, to kill cancer cells. T cells are the immune system’s most potent killing cells due to the fact that they can proliferate and can kill targeted cells serially. The most advanced bi-specific approach is called bi-specific T cell engagers, or BiTE antibodies. BiTE antibodies have two arms, one that connects to a cancer cell, and the other that connects to a T cell. Once both connections have been made, the T cell releases its deadly toxins into the cancer cell.
The most clinically advanced BiTE antibody is blinatumomab from Micromet, Inc., Bethesda, Md.. Blinatumomab is currently in a Phase 1 trial in relapsed/refractory non-Hodgkin’s Lymphoma (NHL) and a Phase 2 study as consolidation therapy in acute lymphoblastic leukemia (ALL). Data from both trials were presented at the European Hematology Association meeting in June 2009.
Data from the Phase 1 NHL trial show that 11 out of 12 patients at the highest dosing cohort experienced a complete or partial response.
The patients included in the Phase 2 ALL clinical trial were in complete hematological remission following intense chemotherapy regimens, but retained a detectable level of ALL cancer cells in their bone marrow, a condition known as minimal residual disease (MRD). Various studies have confirmed that ALL patients with MRD following chemotherapy have a significantly worse prognosis than patients without MRD. At the time of the EHA meeting, 13 of 16 (or 81%) of evaluated patients have shown an MRD response, meeting the trial’s primary endpoint before the completion of the study.
In summary, antibody enhancement represents an approach to improving the clinical performance of these agents in an environment that will demand significant advances in efficacy to be commercially successful. The promise of these agents is evidenced by the early clinical data and the intense development and licensing activity seen in this space.
1. Gilles Andre Salles, MD, PhD et al, “A Phase I/II Study of RO5072759 (GA101) in Patients with Relapsed/Refractory CD20+ Malignant Disease” abstract 234. ASH 2008.
About the Author
Mark Reisenauer is the Chief Commercial Officer and Senior Vice President of Micromet. He holds a B.A. degree in Political Science from the University of Wisconsin.
Filed Under: Drug Discovery