With the initiation in October 2010 of a Phase I (“first in man”) study of the tetravalent, bispecific antibody AFM13 based on its proprietary TandAb® technology, Heidelberg-based Affimed Therapeutics AG has become a clinical drug development company.
In October 2010, Affimed Therapeutics AG announced that it had reached an important milestone in corporate development: The first Hodgkin’s lymphoma patients have been treated with the AFM13 TandAb® antibody in a Phase I clinical trial. Professor Melvyn Little, founder and Chief Scientific Officer, explained: “With this achievement, Affimed, a spin-off of the German Cancer Research Center, is no longer just a preclinical development company but has become a clinical drug developer.” The company’s screening and discovery programmes along with its preclinical antibody research activities have been spun out into a subsidiary (AbCheck s.r.o.).
The TandAbs® that are being tested in a Phase I clinical study are tetravalent bispecific antibody formats developed by Little and his team. The TandAbs® have two binding sites for each antigen and consist exclusively of variable immunoglobulin domains that are connected to each other by linkers. In contrast to other bispecific antibody fragments, TandAbs® are large enough to avoid being excreted too quickly through the kidneys. They have the same avidity and affinity for each target as IgG antibodies, which means that they do not need to be permanently infused during therapeutic application. As they lack constant domains, there is no risk of the Fc regions unspecifically cross-linking with immunoeffector cells/molecules, which could trigger the release of cytokines. Therefore, TandAb® antibodies are not expected to generate severe side effects.
Affimed has developed different kinds of TandAbs® for specific indications. RECRUIT-TandAbs®, with which cytotoxic T-cells or natural killer cells (NK-cells) are recruited, are applied to oncology, and BiBLOCK TandAbs® are able to simultaneously inhibit two targets (e.g., growth factors) in the signalling pathways. BiBLOCK TandAbs® are used for treating autoimmune diseases, asthma or chronic obstructive pulmonary disease (COPF). PROLONG-TandAbs® also bind to serum proteins, which gives the antibodies longer than normal half-lives in the body.
Preclinical studies have shown that RECRUIT-TandAbs® recognise human tumour cells. This cross-linking initiates the killing activity of the respective NK-cell which then leads to the lysis of the tumour cell. AFM13 is a RECRUIT-TandAb® antibody that received in 2009 orphan drug designation for the treatment of Hodgkin’s lymphoma in Europe and the USA. AFM13 binds to the surface antigen CD30 located on the plasma membrane of Reed-Sternberg cells (tumour cells that are characteristic of Hodgkin’s lymphoma) and to the CD16A receptor of NK-cells.
The first of around 40 patients enrolled in the Phase I dose finding study have already been treated with AFM13. So far, the patients have tolerated the antibody very well. Initial results are expected at the end of 2011.
Hodgkin's lymphomas are malignant tumours of the lymph system affecting around 2,000 people annually in Germany and 8,500 in the USA (information provided by the Robert Koch Institute and the American Cancer Society). The lymphomas occur mainly in people aged between 20 and 40 and in people over 70. Hodgkin's lymphoma patients stand a good chance of survival when the cancer is detected at an early stage and treated with chemo- and radiation therapy. Nevertheless, there is huge demand for new therapies, in particular for patients experiencing relapses, as well as those who do not respond to aggressive chemo- and radiation therapy or who do not tolerate the adverse or toxic side effects of chemo- and radiation therapy.
“If the Phase I study leads to positive results and the antibodies prove to be safe, we intend to join forces with a partner to drive the further development forward,” said Dr. Rolf Günther, CEO of Affimed, explaining the company’s business strategy.
Affimed has two more Tandab® antibodies (AFM11 and AFM12) in advanced preclinical development. These are directed against the surface antigen CD19 in connection with CD3 or CD16A. AFM11 will very probably enter clinical Phase I in 2012. The company has plans to develop the antibody as far as Phase IIa (proof of efficacy) before licensing it to other companies. The successful closure of a series C financing round on 29th April 2010 provides the necessary financial means for the project. AFM11 and AFM12 target the treatment of the large and diverse group of non-Hodgkin lymphomas as well as autoimmune diseases such as rheumatoid arthritis. The CD19-positive malignant lymphocytes are destroyed when cytotoxic T-cells or NK-cells are recruited by the TandAb® antibodies. The company hopes that these antibodies will help expand and improve the options for treating non-Hodgkin lymphomas, which are currently primarily treated with the CD20-specific chimerical antibody rituximab (USA: Rituxin; EU: MabThera). In 2008, rituximab achieved revenues of around 5.9 billion US$. Revenues of 8.5 billion US$ are anticipated for 2012 (Financial Times, 2nd October 2008).
In addition to these TandAbs®, Affimed has developed a well-filled pipeline of preclinical TandAb® antibody candidates for a broad range of indications, including:
• AFM15, Affimed's anti-CD3 programme for the treatment of T-cell-mediated autoimmune diseases;
• AFM19, a BiBLOCK- TandAb®, which inhibits two chemokine signalling pathways, for the treatment of asthma and COPD;
• AFM20 and AFM21, specific antibodies against the epithelial cell adhesion protein EpCAM and against the epidermal growth factor receptor (EGFR) for the treatment of solid tumours.
At the beginning of 2010, Affimed transferred its antibody discovery programme and clinical development to its subsidiary, AbCheck s.r.o., located in Pilsen, Czech Republic, in order to fully concentrate on the clinical development of its lead products. As a service company for antibody screening and development, AbCheck offers access to three different phage display libraries that contain around ten billion different fully human scFv antibodies. The subsidiary also has a technology portfolio that covers all steps involved in the production of therapeutic antibodies, from initial research to the optimisation of lead structures.