Mixtures for the Price of Monoclonals
At the meeting, Christian Müller, Ph.D., senior scientist at Symphogen, will talk about his company’s work on antibody mixtures. The idea of using multiple antibodies against a specific target is analogous to the antiviral cocktail approach for treating HIV. “The strategy mimics nature as well, where hundreds of antibodies are produced against antigens,” explains Dr. Müller.
For example Symphogen’s Sym004 Phase II product consists of two antibodies targeting the epidermal growth factor receptor (EGFR) that when combined synergistically inhibit cancer cell growth in vivo and in vitro. In particular, Sym004 leads to extensive internalization/degradation of the receptor. On top of this, Sym004 blocks ligand binding, activation and downstream signaling of the EGF receptor, and activates immune-mediated killing of cancer cells.
Symphogen’s SympressT technology allows production of two or more antibodies in a single batch. First, cell banks are made of stable CHO cell lines each expressing an antibody of the antibody mixture. The cell lines are then mixed, and polyclonal master- and working-cell banks are made, which is the starting point for manufacturing.
Why deal with two differently transfected cells and potential problems upstream and downstream? The alternative, to generate the antibodies separately, is almost twice as expensive as through the Sympress process. Cell culture, harvest, and purification in Sympress proceed as they would for a single monoclonal product, and Symphogen has developed an analytical toolkit around characterization and release of the antibody mixture.
“We use several orthogonal analytic methods drawn from standard antibody work, including ion exchange, reverse phase, and size exclusion analytical chromatography, plus newly developed methods e.g., using mass spectroscopy and quantification of antibody mRNA levels,” says Dr. Müller.
“We’ve had good feedback from FDA and EMA on both manufacturing and analytics.”
The difficulty, and the innovation, involve selecting antibodies that potentiate each other’s function. One would not want proteins that target the same epitope on the target cell, for example, or they would compete with instead of augment each other. The other concerns involve determining the optimal antibody ratio, and then matching the productivity of cells for individual proteins with the desired concentration in the final product.
Since developing medicines like Sym004 requires balancing the effects of two antibodies, it requires some additional preclinical work compared to single antibodies. The potential reward, however, is greater efficacy and much lower cost compared with administration of two separate drugs. So far, according to Dr. Müller, Sym004 “has superior efficacy in preclinical models than cetuximab” (Erbitux), a blockbuster EGFR monoclonal.