Factors To Consider When Licensing An ADC Program
By Tyler Menichiello, contributing editor
Elevation Oncology’s lead program, EO-3021, is a Claudin 18.2-targeting antibody-drug conjugate (ADC) aimed at treating solid tumors. The company gained exclusive rights to develop and commercialize EO-3021 globally (outside of Greater China) from Chinese pharmaceutical company, CSPC Pharmaceutical Group. I recently spoke to Elevation Oncology’s CEO, Joseph Ferra, and CSO, Dr. David Dornan, about this licensing deal. They explained what made EO-3021 worth licensing, and how the company — leveraging clinical data from CSPC — is executing its clinical strategy.
Must-Haves And Nice-To-Haves
Prior to licensing EO-3021, Ferra says the company’s goal was to identify a good target. “We homed in on Claudin 18.2 early on because we thought it was a target with a huge unmet need, and one that was going to become increasingly important for a range of cancers,” he says. Claudin 18.2 is commonly expressed in pancreatic and esophageal tumors, but it’s a particularly relevant target for gastric cancers. While the trial’s dose-escalation phase includes all relevant tumor types, Ferra says the company intends to focus specifically on gastric and gastroesophageal junction (GEJ) tumors in the expansion phase. “We feel strongly that gastric cancer is going to be the price of admission for showing that you have a competitive Claudin 18.2 ADC,” he says.
Of course, identifying a proper target is only half the battle. Since the company didn’t have its own ADC program, the next step was finding a differentiated Claudin 18.2 ADC. According to Ferra and Dornan, CSPC’s platform stood out because of its construct, which utilizes glutamine site-specific conjugation. Conjugation refers to how (and where specifically) a linker-payload is attached to an antibody, and cysteine conjugation is one of the most common methods. According to Dornan, one disadvantage of cysteine conjugation is that it’s subject to a retro-Michael reaction in vivo (i.e., it can be reversed). This leads to a loss of payload over time, which can result in off-target toxicity. “When you conjugate glutamine, you don’t get that retro-Michael reaction,” he explains. “It’s a stable amide bond on the antibody, and that essentially means it can’t fall off.”
“One of those things that was a must-have was technology that minimized the opportunity for payload-associated toxicities,” Ferra says. “CSPC’s program rose to the top because they put a lot of energy into using that glutamine site-specific conjugation to design something that’s truly differentiated.” This differentiated technology, along with specific Claudin 18.2 targeting, covered Elevation’s “must-haves.” The cherry on top, Ferra says, was existent clinical data — a “nice-to-have.”
“Another thing that is a nice-to-have — but close to a must-have — is manufacturing capability,” Dornan explains. “You can drive a fancy car, but if it breaks down every six months, it wasn’t really worth the purchase. That’s what it’s like with novel ADC technology.”
Evaluate Manufacturability
When it comes to determining an ADC’s manufacturability, Dornan says, one of the first considerations is how much the manufacturing process differs from that of other commercially available ADCs. Using EO-3021 as an example, he explains how glutamine conjugation doesn’t differ significantly from cysteine conjugation. “It just uses an enzyme instead of chemistry, but the number of steps is similar,” he says. “In the grand scheme of things, it’s not untenable.”
In the case of EO-3021 (which was a clinical-stage program), there was demonstrated manufacturability — at least at the clinical scale. However, when it comes to evaluating new technologies, it’s important to consider what kind of scale has been achievable thus far.
“Obviously, if it’s an early technology, there’s no way it’s been manufactured at a commercial scale,” Dornan says. “But if you can get up to what we call a pilot scale — taking it from the lab into bigger bioreactors and conjugation sizes while maintaining linearity from scale — then that’s a sign that it’s actually possible to keep going up to the commercial scale.”
Another factor to keep in mind is the availability of reagents. “Make sure that any necessary reagents are actually available; that they don’t have to be mined from out in the middle of nowhere,” Dornan says. Ideally, these reagents can be synthetically derived or purified from abundant sources. “Sometimes there are special resins or special media used in certain technologies that may not be as readily available as we would like, and we tend not to be excited about them in the short term,” he says. Of course, exceptions can be made, and supply chains can be adapted, but it’s important to consider these parameters when licensing a program.
Executing Clinical Strategy
As mentioned earlier, a licensed program’s clinical data falls into the category of “nice-to-have.” In the case of EO-3021, Ferra says having CSPC’s clinical data helped inform Elevation Oncology’s clinical strategy and early decision making regarding its Phase 1 trial. One early decision Ferra points to was not requiring patients to have their solid tumor(s) tested for Claudin 18.2 expression as a prerequisite for trial enrollment.
“Of course, we’re monitoring Claudin 18.2 expression because we want to understand that relative to efficacy, but we’re not requiring it,” he explains. “Every delay takes a toll on the patient and makes it harder for them to get the drug, so if we can skip that step, we’re saving them days and getting more patients on the trial in a shorter period of time.”
The other benefit of having clinical data for EO-3021, according to Ferra, is being able to present it to clinicians. “If we can provide clinicians with evidence — in this case, evidence from a poster that was at ASCO — then they can have the confidence to put their patients on a trial with EO-3021 because it’s clearly being effective.”
For the foreseeable future, Elevation Oncology is focused on progressing EO-3021 through clinical trials. With time (and success), however, the company plans to follow this strategy with other targets and programs. “Job number one, two, and three is execution around EO-3021,” Ferra says. “But embedded in that is continuing to maximize what I think is really our competitive advantage — the knowledge and experience of our team around ADCs.”
As technology improves, ADCs are seeing more clinical success, which only encourages further innovation and ADC development. In 2023 alone, there were 76 deals made in the space. As the ADC space continues to grow, so do the opportunities — and the competition. “There is a lot of opportunity and a lot to work on,” Ferra says, “and the challenge is, we’re not the only ones trying to do it. It’s always hard to be a smaller company and make sure you can punch above your weight. I think we did that with EO-3021 by leveraging not just our knowledge of the technology, but also our prior relationships in order to make the agreement with CSPC a reality. We’re going to continue finding ways to get a leg up on the competition, whether that’s relevant for EO-3021 or for the next program and the program after that.”