The ABCs of ADCs

Pfizer signs antibody-drug conjugate collaboration with Seattle Genetics

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BOTHELL, Wash.—Seattle Genetics Inc. officials soon may be filling out a pretty sizable deposit slip in the form of an $8 million fee from Pfizer Inc. for rights to use its cancer-fighting antibody-drug conjugate technology.

Under terms of the collaboration, Pfizer is responsible for research, product development, manufacturing and commercialization of any ADC products. In addition to $8 million up front, Seattle Genetics is eligible to receive from Pfizer more than $200 million in progress-dependent milestones as well as royalties on worldwide net sales of any resulting ADC products.

Seattle Genetics also will receive material supply and annual maintenance fees as well as research support payments for assistance provided to Pfizer under the collaboration.

The method used by Seattle Genetics makes it possible to combine targeted antibodies with toxins that make them more potent cell-killing agents. In recent years, the company has licensed its ADC technology to a number of biotechnology and pharmaceutical companies in exchange for fees, milestones, upfront payments and royalties on net sales of products incorporating its technology.

ADCs are monoclonal antibodies that selectively deliver potent anti-cancer agents to tumor cells. With more than a decade of experience and knowledge in ADC innovation, Seattle Genetics has developed proprietary technology employing synthetic, highly potent cell-killing agents called auristatins (such as MMAE and MMAF) and stable linker systems that attach auristatin to the antibody.

Seattle Genetics' novel linker systems are designed to be stable in the bloodstream and release the potent cell-killing agent once inside targeted cancer cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing the antitumor activity.

Pacing the company's ADC product line is brentuximab vedotin for lymphoma. The company plans to submit a biologics license application in the first quarter of the year will seek approval for both relapsed or refractory Hodgkin lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma.

According to Hans-Peter Gerber, senior director of Pfizer's BioConjugate/Vascular Biology Oncology Research unit, Seattle Genetics proved to be an attractive partner for the collaboration "because of its auristatin-based drug-linker compounds that are highly potent tubulin poisons that interfere with tubulin polymerization and induce rapid cell death at low picomolar intracellular concentrations."

"About half of the clinical ADC programs currently in clinical development are auristatin-based; hence, clinical experience with this class of ADC payloads is increasing rapidly," he adds.

Gerber says Pfizer isn't permitted to divulge the exact target(s) named in the collaboration.

"Suffice it to say that the Pfizer Oncology Research unit is invested heavily in the discovery of novel tumor-associated antigens, as well as antigens expressed on the host-derived elements that support tumor growth," he says.

Eric L. Dobmeier, chief business officer at Seattle Genetics, says the collaboration "reflects the increasing value of our ADC technology and strong interest in its potential among leaders in the drug development community."

"We now have 10 ongoing ADC collaborations, six collaborator ADCs using our technology are in clinical development and several additional programs are advancing towards the clinic," Dobmeier notes. "We have generated more than $145 million from ADC licensing, and we have the potential to receive significant future milestones and royalties for ADCs developed by our collaborators."

According to Seattle Genetics CEO Clay Siegall, the company uses technology licensing deals as a stable form of funding to support the company's operating expenses, while focusing mainly on developing products for cancer.

Currently, six collaborator ADCs using the company's technology are in clinical development, and several additional programs are advancing toward the clinic. Seattle Genetics' ADC technology collaborators include Bayer Pharmaceuticals Corp.; Celldex Therapeutics; Daiichi Sankyo Co. Ltd.; Genentech Inc.; GlaxoSmithKline; Millennium, a subsidiary of Takeda Pharmaceutical Co. Ltd.; and PSMA Development Co. LLC, a subsidiary of Progenics Pharmaceuticals Inc. The company also has ADC co-development agreements with Agensys Inc., an affiliate of Astellas Pharma Inc., and Genmab A/S.

The success realized by Seattle Genetics has caught the eye of analysts, including Oppenheimer and Co. Inc.'s Bret Holley, who points the increasing licensing value of ADC technology in a recent note: "Additional collaborations such as this highlight the value of Seattle Genetics' ADC technology and should continue to grow the company's revenue base."

This collaboration marks the first partnership between Seattle Genetics and Pfizer, and Gerber notes the company is "very excited about the prospect of merging the cutting-edge technology and expertise available at each company, with the singular goal of creating innovative new medicines for cancer patients."

Gerber notes that cytotoxic cancer drugs have long been a mainstay of cancer therapy, and, unlike many of the more recently developed molecularly targeted agents, the cytotoxic drugs are capable of causing tumor cell death and regression. 

"Unfortunately, the cell-killing effects of these drugs are not tumor specific, and their use is often limited by serious, sometimes life-threatening toxicities to the patient. In principle, ADCs allow for the targeted delivery of cell-killing anticancer drugs to tumor tissues, while reducing the exposure of normal tissues to the drug, thereby reducing adverse side effects in the patient," he explains. "We believe that the partnership with Seattle Genetics will allow Pfizer Oncology to make optimal use of our own internal research into tumor-associated antigens, as well as antibody production technologies, for the development of innovative ADCs."

Gerber notes that the alliance doesn't necessarily fill a void in Pfizer's pipeline as much as it expands into a space where the drug maker has already achieved clinical success.

"We have Mylotarg, the first clinically approved ADC, and a second ADC, Inotuzumab Ozagamicin, in clinical development for non-Hodgkin's lymphoma," he notes. "However, the Seattle Genetics partnership offers access to a different linker-payload combination than we have employed in the past."

Pfizer signs separate agreements with Lpath, Phylogica

NEW YORK—In late December, Pfizer Inc. signed deals with two additional companies: one with San Diego-based Lpath for a product candidate to treat ophthalmology disorders, and the other with Australia's Phylogica to discover peptide-based vaccines.

Lpath will provide Pfizer with an exclusive option for a worldwide license to develop and commercialize iSONEP, which is being evaluated for the treatment of wet age-related macular degeneration and other ophthalmology disorders. Pfizer will provide Lpath with an upfront option payment of $14 million in addition to sharing the cost of the planned Phase Ib and IIa trials. Following completion of the studies, Pfizer has the right to exercise its option for worldwide rights to iSONEP for an undisclosed option fee. If Pfizer exercises its option, Lpath will be eligible to receive development, regulatory and commercial milestone payments that could total up to $497.5 million, as well as tiered double-digit royalties based on sales of the product.

As part of the agreement, Lpath has granted to Pfizer a time-limited right of first refusal for ASONEP, Lpath's product candidate that is being evaluated for the treatment of cancer. Two Phase IIa trials are currently planned to further assess ASONEP's efficacy and safety in cancer patients.

The Phylogica collaboration and licensing agreement involves the discovery of novel peptide-based vaccines. Phylogica will employ its Phylomer drug discovery platform to identify peptides suitable for further evaluation. Under the agreement, Phylogica will grant Pfizer certain rights, including an option to license any resulting Phylomers for further research, development and commercialization of novel peptide-based vaccines.

Phylogica will receive an upfront payment of $500,000 and is eligible to receive a commercial license payment. In addition, it is eligible to receive preclinical, clinical and other milestone payments of up to $134 million and royalties on worldwide sales. ddn



Takeda Pharmaceutical Company Ltd.

Progenics Pharmaceuticals Inc.

Agensys Inc.

Astellas Pharma Inc.

Genmab A/S

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