Of warheads and wellness
August 2012
by Jeffrey Bouley  |  Email the author


LONDON—Cancer Research Technology (CRT), the commercial arm of Cancer Research UK, and recent startup ADC Therapeutics Sarl (ADCT) in Lausanne, Switzerland, in early July signed agreements to develop antibody-drug conjugates (ADCs) using CRT antibodies and peptides, and ADCT's "warhead" and linker chemistries, to fight cancer.
The warheads coming out of ADCT—which was recently established with $50 million from Celtic Therapeutics, a private equity firm, to develop a pipeline of as many as 10 new therapies based on ADCs—are based on proprietary technology around pyrrolobenzodiazepines (PBDs) that was developed by London-based Spirogen Ltd. It was in March of this year that ADCT and Spirogen announced a partnership to develop proprietary ADC products, and that connection to Spirogen provides a dual link for ADCT to CRT and Celtic, as some of the technology that went into Spirogen's formation was originally financed by Cancer Research UK academic funding, and Celtic is a major investor in Spirogen, notes Laura Fletcher, associate director of business management at CRT.
"Over the years we've had all kinds of dialogue with Spirogen, and a couple years ago, we started looking at whether CRT had access to targeting agents that might fit well with their ADC technology," Fletcher tells ddn. "With the founding of ADC Therapeutics, those discussions pretty much transferred over to them, but much of the management team is shared between ADCT and Spirogen, so there's significant overlap and continuity. Many aspects of the current agreement are extensions of deals we formed a year ago or more with Spirogen to work on promising targeting agents and the current agreements are to take the work into the in-vivo realm."  
ADCT will initially fund preclinical studies for the new ADCs in a range of cancer models, but other deal terms were not disclosed, nor are the cancer targets a matter of public discussion yet.  
However, Fletcher did share that, "The agents we are looking at are against targets that have not yet been tested in the ADC arena, which fits well with CRT's goal to fill gaps and explore areas that others haven't— that makes this deal fit the box very well for us." ADCs are a clinically important class of oncology drugs because they combine the specificity of antibodies with novel warhead chemistries, note ADCT and CRT. The antibody component selectively targets the cancer cells to deliver tumor-destroying chemicals that are internalized into the cancer cell while avoiding damage to healthy tissue. Once inside the cancer cell, the linker degrades and the active toxin is released, binding to the cell's DNA and killing the cancer cell. ADCT's toxic chemicals interact with DNA without disrupting the double helix structure that avoids triggering DNA repair processes. In part, it is hoped that this will prevent drug resistance.
"ADCs are receiving a lot of attention at the moment, in part because Seattle Genetics got an ADC product approved recently, plus there's another product [Roche's Trastuzumab-DM1] showing promise in clinical studies," Fletcher explains. "There is a lot of attention on the potential for ADCs to strike a therapeutic blow and take toxins straight to the source to eliminate tumors. It's a field that has generated great excitement, so it's a great time to be involved in this area."  
"We are very excited to see our potent PBD-based warheads combined with CRT's leading tumor-targeting antibodies and peptides," said Dr. Chris Martin, ADCT's collaboration manager and CEO of Spirogen, echoing Fletcher's upbeat attitude in the news release about the deal. "Together, we are committed to faster and more efficient drug development, and have already commenced our preclinical work for these exciting programs. We believe this provides a very promising and rapid route to develop novel ADCs for cancer therapy and are very much looking forward to working in partnership with CRT."
Calling the collaboration "unique," Dr. Phil L'Huillier, CRT's director of business management, said in the same news release that the collaboration "marries ADCT's targeted portfolio with CRT's access to world-class cancer research supported by GBP 334 million each year. We hope the collaboration will identify a range of ADCs that can be taken forward for development into innovative new ways to treat cancer and save lives."  
While the collaboration is an important one, Fletcher emphasizes it isn't the only iron that CRT has in the fire.  
"This is not an exclusive relationship by any means, but it's great to have an avenue through which to explore these three agents and maybe similar ones in the future, whether with ADC Therapeutics or others," she says. "Also, this collaboration shouldn't be taken to mean that CRT is tied to ADC therapies in general, either. We welcome and seek other partners and other kinds of agents."  

Cancer Research Technology and BioInvent in oncology deal  
LONDON—Cancer Research Technology Ltd. (CRT) also announced last month that it has entered into a collaboration with BioInvent International AB and Queen Mary, University of London, to identify new therapeutic antibodies in oncology.  
BioInvent and scientists funded by Cancer Research UK at Queen Mary, under the leadership of Dr. Thorsten Hagemann, Senior Cancer Research UK Fellow, will jointly be looking for new therapeutic targets by applying BioInvent's F.I.R.S.T. technology, a functional approach to therapeutic antibody discovery. Hagemann and his team will provide the collaboration with biological pathways for the development of new oncology therapies.  
The F.I.R.S.T. platform, through its biopanning technology, enables identification of functionally superior antibodies across multiple targets overexpressed by target cells. This combined target and drug discovery platform utilizes primary cancer patient cells, rather than recombinant proteins, as an antigen source allowing for discovery of novel specificities (receptors and epitopes) and target receptor functions. 

The agreement gives BioInvent the option to enter into licenses to bring forward drug candidates beyond lead candidate identification in exchange for milestones and royalties to CRT.
"By combining the preclinical expertise in animal models within my laboratory and our access to patient samples with BioInvent's F.I.R.S.T. technology we hope to speed up the discovery and development of new possible treatments," said Hagemann in a news release announcing the partnership. "We will focus primarily on targets which affect the pro-tumor role of myeloid cells in solid malignancies, an area in which my lab has developed significant experience. We would anticipate such therapies to be applicable across a range of tumor types."  
"It is of major importance for BioInvent to tap into the vast knowledge base of a multi-pronged organization such as Cancer Research Technology," added Björn Frendéus, BioInvent's vice president of preclinical development. "One of our first areas of interest will be in the biology of myeloid cells in cancer, which has been an area of focus for us for many years."  
Code: E081205

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