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European Biopharmaceutical Review

The Quest for Cures

Mark Reisenauer at Micromet Inc reviews next-generation antibody approaches to cancer treatment

Therapeutic antibodies have become one of the largest and fastest growing drug classes in pharmaceuticals over the last decade. In the cancer market, antibodies have become an integral component of treatment regimens that have improved and extended the lives of cancer patients. In haematologic cancers, Rituxan, in combination with chemotherapy, has become the standard of care in many non-Hodgkin’s lymphoma (NHL) subtypes due to the improved efficacy that it adds to chemotherapy regimens. In solid tumours, Avastin, in combination with chemotherapy, is becoming a standard of care in colorectal, non-small cell, breast and renal cancers.

The clinical success of antibodies to treat cancer has translated into significant commercial success. Antibody oncology sales are forecasted to be over $27 billion by 2018 in the seven major markets. Despite these advances, however, there remains a significant unmet need in cancer treatment: very few ‘cures’ are achieved with cancer therapy. There is clearly much room for improvement in antibody approaches to cancer.


This unmet need, coupled with the commercial attractiveness of the oncology market, has led to a significant number of drugs in development. Oncology is one of the most attractive therapeutic markets; it is profitable due to low sales and marketing expenses and relatively high drug prices. There are 861 drugs in development to treat cancer, many of which are antibody-based (1). This is the most drugs in development of any therapeutic area.

The cancer antibody space is also attractive from a commercial and licensing perspective because several of the leading antibodies are likely to face biosimilar competition in the near future. For example, Rituxan, Herceptin and Erbitux will lose their exclusivity between 2011 and 2020. As companies seek to develop nextgeneration antibodies, they will be faced with significant development and commercialisation challenges. Success in the future will be defined much more stringently than in the past. For antibodies, product profiles will need to be much more differentiated due to biosimilars and the changing pricing and reimbursement landscape. Small incremental improvements in efficacy and safety will not be rewarded in the marketplace as they were in the past. New antibody approaches will need to show significant improvements in efficacy in order to command significant utilisation and premium pricing. Companies are pursuing three types of enhancements to antibodies in search of improved product profiles. These enhancements include bi-specifics, tuned and conjugated.


The first antibody enhancement approach is bi-specifics. The most advanced bispecific approach is called bi-specific T cell engagers, or BiTE antibodies. BiTE antibodies utilise 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 their ability to proliferate and kill targeted cells serially. 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. Blinatumomab targets CD19, which is found in many B cell haematologic malignancies. Blinatumomab is currently in a Phase I trial in relapsed/refractory NHL and a Phase II study as consolidation therapy in acute lymphoblastic leukemia (ALL). Data from both trials were presented at the American Society of Hemotology (ASH) annual meeting in December 2009. Data from the Phase I NHL trial demonstrate the potency of the BiTE antibody approach. The data show that 100 per cent of evaluable patients (12 out of 12) responded after receiving a dose of 0.06mg/m2 per day after the first treatment cycle of four to eight weeks (2).

The patients included in the Phase II ALL clinical trial were in complete haematological 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. The primary endpoint of the Phase II study is MRD response within four cycles of treatment. MRD response is defined as the elimination of ALL cancer cells in patients with MRD below the limit of detection. The achievement of the primary endpoint in the Phase II study requires that at least 22 per cent of 21 patients have an MRD response. At the time of the ASH meeting, 80 per cent of the evaluable patients (16 out of 20) achieved an MRD response, all within the first treatment cycle. Importantly, the responses appear to be durable, with patients free of relapse for currently upto 15 months (3). The BiTE antibody approach appears to be a very potent method of treating cancer. Further clinical development is required to elucidate blinatumomab’s product profile.


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 is the development of GA101 from Glycart and Roche. GA101 is a humanised anti-CD20 monoclonal antibody engineered to increase target cell death. This compound is in Phase I/II trials for NHL and chronic lymphocytic leukemia (CLL). Phase I data presented at the ASH meeting in 2009 showed that GA101 produced a 43 per cent overall response rate in relapsed/refractory NHL patients (4).


Conjugated antibodies are the third method of antibody enhancement currently being explored by pharma. Conjugated antibodies contain cancer killing agents such as chemotherapy, toxins or radioisotopes. The rationale for this approach is that the antibody can bring the cancer killing agent directly to the cancer cell with minimal damage to nearby healthy cells. Conjugated antibodies have experienced limited success as a result of toxicity issues and complicated methods of administration. The toxicity has arisen from the fact that the toxic payload is often delivered to both cancerous and healthy tissues. Examples of conjugated antibodies include the radioimmunotherapies Bexar and Zevalin and the drug-conjugated antibody Mylotarg. More recent approaches in development appear to largely avoid these unwanted side-effects.


Development approaches for antibodies are evolving to reflect the targeted nature of cancer treatment. Companies are pursuing niche indications that would previously have been avoided due to a lack of commercial potential. The advantages of pursuing niche indications, especially for a compound’s first indication, are numerous, and include an unencumbered regulatory pathway, few competitors, the ability to conduct single arm trials with response rate as an endpoint and premium pricing. Companies can then expand development beyond these niche indications to maximise the potential of their products. Several antibodies and targeted small molecules have been clinically and commercially successful with this approach, including Herceptin, Gleevec and Rituxan.

In addition to the high level of activity in antibody development, novel antibodies are an area of intense licensing activity and interest. There are several reasons for this level of interest. First, these therapies have the potential to extend the life cycle of successful antibody products. A prime example is trastuzumab DM-1 from Immunogen. This compound is a conjugated version of Herceptin. Trastuzumab DM-1 was licensed to Genentech as a life cycle management approach to the impending patent expiration of Herceptin. Additionally, these approaches provide risk mitigation by diversifying a company’s product pipelines. By utilising different approaches and mechanisms against similar targets, the high risk of failure can be mitigated.


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 demonstrated by the early clinical data and the intense development and licensing activity seen in this space.


  1. PhRMA 2009 Report, Medicines in Development for Cancer
  2. Nagorsen D et al, Confirmation of safety, efficacy and response dration in non-Hodgkin’s lymphoma patients treated with 60 microgram/square meter per day of BiTE antibody Blinatumomab, ASH annual meeting, abstract number 2,723, 2009
  3. Topp M et al, Report of a Phase II trial of single-agent BiTE® antibody Blinatumomab in patients with minimal residual disease (MRD) positive B-precursor acute lymphoblastic leukemia (ALL), ASH annual meeting, abstract number 840, 2009
  4. Salles G et al, Phase I study of RO5072759 (GA101) in patients with relapsed/refractory CD20+ non- Hodgkin lymphoma (NHL), ASH annual meeting, abstract number 1,704, 2009

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Mark Reisenauer has served as Micromet’s Chief Commercial Officer since September 2007. He joined Micromet from Abbott, where he was the General Manager of the Oncology Franchise from 2002 to 2006, and most recently Divisional Vice President and General Manager of the Neuroscience franchise from 2006 to September 2007. Before joining Abbott, Mark was the Director of Marketing for Breast Cancer (Portfolio Lead) and the Director of Breast Cancer Products at Pharmacia from 1999 to 2002. From 1997 to 1999, he was the Associate Director of Oncology Global Marketing at Bristol-Myers Squibb and from 1988 to 1997 held various positions in sales and oncology marketing at Zeneca.
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