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ADC Therapeutics Gets $50M for Antibody-Drug Conjugates

bwt03272012 ADC

By Cormac Sheridan
Staff Writer

Start-up firm ADC Therapeutics Sarl has secured funding commitments of up to $50 million to take forward 10 antibody-drug conjugate programs in oncology, based on conjugate and linker chemistry developed by London-based Spirogen Ltd.

New York-based Celtic Therapeutics Management LLLP, Spirogen's majority shareholder, is also the majority shareholder in the new venture, which is based in Lausanne, Switzerland. Other backers include founding investors in London-based Spirogen and Cancer Research Technology Ltd., the technology commercialization arm of Cancer Research UK.

The new venture represents a vehicle for funding the development of a proprietary drug pipeline based on Spirogen's technology.

"Spirogen's model up to now has been to license our technology to Genentech and other companies," Spirogen CEO Chris Martin told BioWorld Today. The company last year entered a preclinical collaboration with Genentech – a subsidiary of Basel, Switzerland-based Roche AG – based on antibodies supplied by Genentech. (See BioWorld International, Jan. 12, 2011.)

ADC has so far either in-licensed or is in late-stage negotiations for seven of the 10 tumor-targeting antibodies it has prioritized following a consultation process with an advisory board chaired by Neil Bander of Weill-Cornell Medical College in New York. Those molecules will be "weaponized" with pyrrolobenzodiazepine (PBD) derivatives developed by Spirogen.

The latter firm already is developing one such molecule – SG2000 – as a standalone small-molecule drug. A Phase II trial in cisplatin-resistant ovarian cancer is under way and is expected to report in late 2012 or early 2013. "They have a therapeutic index in their own right," Martin said.

PBDs originally were discovered in the 1960s, but further development was delayed until the 1980s when Spirogen co-founders David Thurston and Philip Howard found a way to to make PBD dimers. "They proved to be very significantly more effective than monomers," Martin said.

PBDs act by binding the minor groove of DNA molecules. Another Spirogen co-founder, John Hartley of University College London, showed that the resulting cross-linked adducts do not distort DNA's helical geometry and thereby evade detection by the cell's nucleotide excision repair (NER) system. That should ensure a more potent effect than those exerted by other cross-linking drugs, such as cisplatin and melphalan, which create bulky DNA adducts that are more readily identified.

Up-regulation of the NER pathway is thought to be a treatment-resistance mechanism in certain cancers.

ADC is not yet disclosing details of the linker chemistry it is using to connect its in-licensed antibodies with their cytotoxic payloads. The company has access to multiple linkers and to multiple PBDs, so it, theoretically, can generate a large number of antibody-drug conjugates per target.

"If you take the whole universe of PBDs we've made and linker chemistries we've worked with, it does run into the hundreds," Martin said. In practice, the firm will work initially with about a dozen different constructs per target, but will only do detailed work on around half of them.

The new initiative has been under consideration for several years. Its backers have taken encouragement from the progress of Seattle Genetics Inc., of Bothell, Wash., which gained approval last year for Adcetris (brentuximab vedotin) in several lymphoma indications, and of ImmunoGen Inc., of Waltham, Mass., which is in a partnership with Genentech on T-DM1 (trastuzumab emtansine), a construct that is undergoing Phase III trials in breast cancer. (See BioWorld Today, Aug. 22, 2011.)

The steady accumulation of data on antibodies, linker chemistry and cytotoxic payloads has made the whole approach feasible at this point.

"The real challenge is each component of the system has its own dynamics," Martin said.

Antibody avidity and affinity need to be optimized, as does antibody internalization. Chemical linkers need to be sufficiently stable to ensure that minimal amounts of drug are lost while the antibody remains in circulation. The maturation of analytic technologies for characterizing the structure of antibody-drug conjugates and monitoring their activities has been another important factor in the development of the field, Martin added.

The company aims to move 10 programs into preclinical assessment over the next 12 months and to take a lead program into the clinic within two years. Its business model is based on finding development partners after obtaining clinical proof of concept. "The business plan is fully funded," Martin said.

Celtic Therapeutics partner Michael Forer has been appointed CEO of ADC Therapeutics.

Although based in Switzerland, the company's initial lab work will be performed by Spirogen and its network of service providers.