Straight A's with ADCs

Astellas, Ambrx to collaborate on ADCs for oncology targets

Kelsey Kaustinen
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TOKYO—In a deal that is as matched in expertise andtechnology as it is in alliteration, Astellas Pharma Inc. and Ambrx Inc. haveannounced a collaboration to discover and develop novel antibody drugconjugates (ADCs) against oncology targets.
Per the terms of the collaboration, Astellas will pay Ambrx$15 million up front, with the potential for an additional $285 million innear- and long-term research, development, regulatory and sales milestones foran undisclosed number of oncology targets. A fraction of the milestones, inaddition to royalties on net sales, will be contingent on the successfulcommercialization of any products that result from this collaboration. Astellaswill gain worldwide rights to develop and commercialize ADCs for oncology. Thespecific oncology targets were not disclosed.
"Agensys Inc., an affiliate of Astellas which specializes intherapeutic antibody research and development in cancer, has significantexperience with ADCs as oncology therapeutics and is looking to further expandits capabilities in this area," Dr. David Stover, senior vice president andAgensys site head, said in a press release. "Ambrx offers a novel approach toallow creation of site-specific and highly stable conjugations that have thepotential to further optimize drug delivery to tumor cells."
The collaboration represents the first time the twocompanies have worked together, and Dr. Lawson Macartney, CEO of Ambrx, saysthe agreement is built on a mutual attraction. Astellas, he notes, "has afabulous reputation in being a leading company in the oncology space," andAmbrx brings with it the specificity of its proprietary technology.
"As part of their expertise in oncology, Astellas, throughtheir subsidiary Agensys, actually have multiple antibody drug conjugatemolecules in the clinic," adds Dr. Ho Sung Cho, chief technology officer atAmbrx. "And so we thought that by bringing on a partner that also had specificexpertise in this novel modality, they could truly value what we can createtogether, and so we look forward to enabling them to put additional moleculesinto clinical evaluation."
ADCs are composed of an antibody and a payload drug, andenable targeted delivery of drugs. Ambrx's approach combines site-specificconjugation technology with proprietary payloads and links, and the companynotes on its website that "by using conjugation chemistries that are orthogonalto the native 20 amino acids, we create antibody conjugates with unprecedentedhomogeneity with respect to the site of drug attachment."
The company's ADCs have been shown in preclinical usage tohave high potency and a wider therapeutic index than ADCs created withconventional non-specific conjugation.
Macartney notes that traditionally ADCs have not always beensuccessful because the antibodies have been conjugated with the drug attachedwherever it could get purchase, with the result that sometimes the payloadwould obstruct the interaction between the antibody and the tumor-specificmolecule. Ambrx's approach, what he calls "medicinal chemistry for proteins,"allows them to place a unique molecule—what they call a non-natural aminoacid—at very specific points along the antibody, which allows them to "increasethe potency and minimize the side effects."
"That balance, between therapeutic effects and side effects,that's what we call the therapeutic window. You want that window to be as wideas you can, and we believe that we optimize the therapeutic window for anygiven antibody drug conjugate," says Macartney.
Ambrx has other large industry partnerships underway thatMacartney says are progressing "absolutely on track." Ambrx is working withBristol-Myers Squibb Co., in a partnership that began in September 2011, on twobiologics. One, ARX618, is based on Ambrx's research in Fibroblast GrowthFactor 21 and is being developed in diabetes, and the other is based on theRelaxin hormone, which is currently under development for the treatment ofheart failure. Ambrx is also collaborating with Merck, in a deal that wasannounced last June. The two companies are developing biologic drug conjugatesagainst undisclosed targets.

Kelsey Kaustinen

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