CytomX Therapeutics Inc.'s oncology deal with Pfizer Inc. to develop Probody-drug conjugates (PDCs) gives the pharma giant rights to develop selected candidates in exchange for a potential $25 million up front, as well as $610 million if regulatory and sales milestones are met, and tiered royalties into the double digits on sales of resulting products.

The $25 million "incorporates the up-front research funding and near-term milestone payments, as we move [PDCs] through various stages of preclinical evaluation," said Sean McCarthy, CEO of South San Francisco-based CytomX. "It requires us to meet certain milestones to achieve the full amount, but it's a number that is realizable."

New York-based Pfizer is responsible for development and commercializing PDCs, though the pair will work on preclinical research together. "It's our first such deal, and we were careful to wait for the first deal to be the right deal," McCarthy told BioWorld Today.

Probodies – locally activated antibodies that bind to target antigens only in disease tissue – could be useful across varying disease indications, since the technology can be applied to other proteins and peptides. CytomX, though, has been focused on cancer since starting up in 2008, and it raised $30 million through a Series B financing in 2010. Canaan Partners joined as funders in the summer of 2012, adding $11 million to the Series B. (See BioWorld Today, Sept. 23, 2010.)

"What we offer is really a disruptive approach to ADCs, particularly as it pertains to target selection," McCarthy said. "We have realized over the last couple of years, that this idea really has application in a number of different areas of antibody therapeutics."

Along with Probodies and PDCs, "there are also, we're pretty convinced, other bispecific or potentially even multispecific formats where target-antigen combinations have great efficacy potential, but are likely to be limited by adverse events. In each of these areas, the Probody approach allows you to think differently about how you select targets. That's particularly important in ADCs, because much of the low-hanging fruit in the target space has been picked already. There are really very few examples of antigens that are selectively expressed in tumor tissue and not present elsewhere."

Pfizer's collaboration with CytomX closely follows last month's fizzle of the Phase III trial with inotuzumab ozogamicin, the ADC composed of a monoclonal antibody targeting CD22, administered in combination with Rituxan (rituximab, Roche AG and Biogen Idec Inc.), in relapsed or refractory CD22-positive aggressive non-Hodgkin's lymphoma (NHL). (See BioWorld Today, May 22, 2013.)

NHL work with the compound stopped after an independent data monitoring committee concluded, during a scheduled interim analysis, that the treatment would not meet the primary endpoint of improving overall survival compared with bendamustine plus rituximab or gemcitabine plus rituximab (investigator's choice). Pfizer is forging ahead with the ADC in an open-label, randomized, Phase III INO-VATE ALL study, enrolling adults who have relapsed or refractory CD22-positive acute lymphoblastic leukemia. "They have a multipartite approach to building broad capability in ADCs, and I think our approach dovetails very nicely with [it]," McCarthy said. "That's how this deal came together."

Enthusiasm for ADCs seems unlikely to abate soon. San Diego-based Ambrx Inc.'s site-specific ADC platform drew Bristol-Myers Squibb Co., of New York, for a third deal in May. BMS provided $15 million up front plus funding for discovery and research, as well as milestone payments that could total $97 million per oncology product resulting from the arrangement. The relationship between the firms goes back to 2011. Both previous tie-ups involve Ambrx's protein medicinal chemistry technology, one targeting fibroblast growth factor 21 for Type II diabetes and the other focused on the relaxin hormone for the treatment of heart failure. BMS is developing both. (See BioWorld Today, Sept. 23, 2011, and May 6, 2013.)

CytomX could do worse than emulate the likes of Ambrx, which in April inked a cancer pact with Tokyo-based Astellas Pharma Inc., garnering $15 million up front and up to $285 million in potential near- and long-term research, development, regulatory and sales-based milestones for an undisclosed number of ADC targets. Ambrx also has a potential $303 million agreement with Whitehouse Station, N.J.-based Merck & Co. Inc. to design and develop rationally optimized biologic drug conjugates. (See BioWorld Today, April 8, 2012, and June 19, 2012.)

"We're effectively redefining the target landscape" in ADCs, McCarthy said, and more deals lie ahead. "We really haven't mapped out a specific number of [hoped-for] deals," he said. "There are a number of different Probody formats in addition to PDCs. We're in exploratory conversations with various groups."

On its own, CytomX expects to enter the clinic with a drug candidate in 2015, though the firm has "not made a final decision on which program that will be," McCarthy said.