Therapeutics


Figure 1: The mechanism of action for MOR103


Continued from page 50


11 Almagro, JC and Strohl, WR: Antibody Engineering: Humanization, Affinity Maturation and Selection Techniques in Therapeutic Monoclonal Antibodies: From Bench to Clinic 12Van den Brulle, J, Fischer, M, Langmann, T, Horn, G, Waldmann, T, Arnold, S, Fuhrmann, M, Schatz, O, O’Connell, T, O’Connell, D, Auckenthaler, A, Schwer, H. A novel solid phase technology for high-throughput gene synthesis. Biotechniques. 45(3):340-3, 2008.


Thus, the combination of the described high- throughput gene synthesis technology with a synthet- ic human Fab library enables the individual design of each CDR cassette for a variety of properties, such as high affinity and low immunogenicity, and it is appli- cable to all antibodies within the library.


Antibodies in clinical development – a snapshot


A large number of fully human mAbs based on the described antibody library technology are current- ly in clinical and preclinical development in a vari- ety of different therapeutic areas including oncolo- gy, autoimmune disease and inflammation, cardio- vascular diseases, infectious diseases and diseases of the central nervous system.


One of the programmes currently in clinical devel- opment is MOR103 (Figure 1), a treatment for rheumatoid arthritis which is a disease affecting six million people worldwide. This chronic inflammatory autoimmune disease is mediated by GM-CSF, a growth factor for white blood cells. GM-CSF is found in high levels in inflamed joints and its suppression has shown a therapeutic effect in established rheumatoid arthritis animal models. GM-CSF contributes strongly to the release of other signalling molecules and binds to its complementary receptor on the surface of spe- cific immune cells in the joint, stimulating their activa- tion and proliferation. MOR103 is a fully human mAB that was developed with the HuCAL technology and has a high affinity to human GM-CSF. Studies with MOR103 have shown that it neutralises human GM-CSF and inhibits downstream signalling of the GM-CSF receptor. MOR103 is currently in Phase Ib/IIa in patients with active rheumatoid arthritis. Other indications for this antibody include Multiples Sclerosis (MS), a disease which is characterised by ele- vated levels of GM-CSF in its active phase. A more unconventional use for therapeutic anti- bodies is passive immunisation for the treatment of


52


infectious diseases. The discovery and successful implementation of antibiotics have historically pushed therapeutic antibodies for the treatment of infections aside. But the emerging problem of antibiotic resistance has boosted the search for alternatives, namely for treating infections caused by micro-organisms including drug-resistant methicillin-resistant Staphylococcus aureus (MRSA), a growing public health concern associat- ed with increasing levels of mortality. The advan- tages of antibody-based therapy with humanised or human antibodies include high specificity and low toxicity. Antibodies targeting molecules that are associated with Staphylococcus aureus infec- tions, including MRSA, are currently being identi- fied to investigate effective alternative treatment options for antibiotic resistant infections.


Outlook


The recent advances in recombinant antibody tech- nology, such as the maturation of selection plat- forms and the development of automated high- throughput technologies that can be combined with more and more sophisticated antibody affinity mat- uration processes, will continue to advance the development of therapeutic antibodies.


DDW


Dr Markus Enzelberger is a chemist by training; he received his PhD from the University of Stuttgart on the directed evolution of industrial enzymes. Markus did his postdoctoral studies with Stephen Quake at the California Institute of Technology where he worked on new microfludic systems and its application in high throughput screening of bio- logics. He continued this work at Mycometrx Inc, South San Francisico. Markus has been with MorphoSys for nine years and currently holds the position of a Vice President R&D. He is responsi- ble for all partnered antibody discovery projects and technology development.


Drug Discovery World Winter 2010/11


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