Symphonies of antibodies: Advancing precision medicine through combination

Symphogen, based in Denmark, is a private clinical-stage pharmaceutical company with a focus on the use of mixtures of monoclonal antibodies in the precision treatment of cancer.

There can be wide variations in the populations of cells in a tumour and its metastases, or even within a single tumour, and these differences can lead to cancers becoming resistant to treatment. This means that many patients who initially respond to monoclonal antibody-based therapies will eventually relapse. Symphogen's approach to treatment, which uses mixtures of different monoclonal antibodies described as 'symphonies', could address this diversity and tackle treatment resistance.
"We see this as mimicking the human body's immune response, where a reaction to a complex virus can involve 25 to 35 antibodies," said Martin Olin, Symphogen's CEO. "This approach will help us to target the increasing need for precision medicine, particularly in cancer."

Creating therapeutics
Symphogen uses its platform technologies to select mixtures of monoclonal antibodies that are directed at targets on cancer cells and in the tumour microenvironment, and on immune cells.
"We use a combination of different approaches, including functional screening and lead selection to create combinations of monoclonal antibodies that may not have activity alone, but have an additive or even synergistic effect when they are used together," said Olin.
Symphogen's lead program focuses on receptor tyrosine kinases. The lead antibody mixture, Sym004, is a mixture of two recombinant monoclonal antibodies, futuximab and modotuximab, and targets the EGFR receptor, which can be involved in the development of resistance. This is in phase 2 in metastatic colorectal cancer and recurrent glioblastoma multiforme. It is also in phase 1 in squamous non-small cell lung cancer in combination with PD1 inhibitors, and in colorectal cancer with chemotherapy.
"These two antibodies bind to non-overlapping antigens on EGFR and lead to internalisation and break down of the receptor, but only in combination," said Olin. "We have evidence that eliminating the receptor can reverse resistance to EGFR-targeted therapies even in patients that have relapsed two or more times."
Both in Phase 1, Symphogen's Pan-HER candidate, Sym013, is a combination of six antibodies against EGFR, HER2 and HER3, creating a horizontal blockade and closing down the escape mechanism and Sym015 combines two antibodies targeting MET.
"While many companies are developing antibody and bispecific therapeutics, and some are looking at combinations of monoclonals, we believe we are the most advanced in mixtures of antibodies," said Olin. "Our full length antibodies don't have the space challenge seen with bispecifics, and could be used with payloads, or in mixtures with as many as 20 antibodies."

Working in collaboration
Symphogen currently has two key partnerships. The first was signed with Genentech back in 2008, to develop antibody therapeutics against infectious disease. Genentech is assessing a lead in Phase 1 trials. More recently, in January 2016, Symphogen set up a research collaboration with Baxalta (now Shire) to develop and commercialise antibody therapeutics in cancer. This immunooncology-focused partnership is looking at six checkpoint targets, and could file one or two INDs in 2017.
Symphogen is looking for further partners, including those with late stage development and commercialization capabilities.
"Our strategy is to get products to the market, and we would look for partners, but try to keep marketing rights in certain areas by creating regional deals. We will also look for technology partners outside our core disease area," says Olin.


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