It’s only been nine years since Kevan Shokat’s group at the University of California, San Francisco published the seminal paper breaking the “undruggable” spell thought to ensnare KRAS, one of the most common oncogenes. In less than a decade — breakneck speed by drug development standards — the space went from utterly barren to having one approved drug, plus a close rival ready to duke it out.
But as the latest data from Amgen and Mirati out of #ESMO22 illustrate, existing drugs targeting KRAS G12C mutations, modeled on the covalent inhibitors Shokat pioneered, still left glaring gaps in efficacy. And just as with any kind of targeted cancer therapies, resistance continues to loom on the horizon.
Shokat is now proposing a new strategy to hit the KRAS target — hinged directly on the covalent binding he first discovered.
This time around, he’s leaning on the expertise of a colleague, Charly Craik, in antibody engineering, to create bispecific T cell engagers to go after cancer cells that are bound by KRAS G12C inhibitors. Essentially, the idea is that these targeted drugs can spur the creation of certain antigens that can then be used to guide an immune attack on tumors.
Barry Selick
The research,
published in a
Cancer Cell
paper
, points to a “second generation KRAS targeted therapeutic that will ‘pick up’ where the first generation proves no longer efficacious,” said Barry Selick, a seasoned biopharma exec who’s now UCSF’s vice chancellor of business development, innovation and partnerships.
With the backing of Selick’s InVent fund, Shokat and Craik — along with the young scientists leading the work — are launching a biotech upstart named Hap10 Bio.
As Shokat tells it, he’s been pleasantly surprised by how each of the KRAS drugs out there seems to be working.
“Now we get greedy,” he said.
The project started five years ago, when Ziyang Zhang came to Shokat’s UCSF lab as a postdoc. While learning about the mechanism of covalent drugs (“I actually pretended to be a grad student and attended Kevan and Charly’s classes,” he said), he became curious about what happens to the drugs after they engage their target.
“It’s got to go somewhere,” Zhang said. “It can’t just always stay within the cell.”
Soon, he realized it’s a question that scientists and immunologists have pondered for years. The process is known as haptenization, haptens being small molecules that, when attached to a larger protein, may trigger an immune response.
“The idea is that some covalent modifiers can engage host proteins, and there’s always this hypothesis that haptens will generate — will elicit some sort of immune response because this molecular signature will be new to our immune system,” he said.
There’s a twist: In scientific literature, haptenization is usually viewed as something negative, Shokat noted, with worries that an immune response will lead to liver damage and other side effects.
Together with Peter Rohweder, a PhD candidate in Craik’s lab whom Zhang met in classes, Zhang began exploring ways to leverage that process for a potential therapy. He started off with experiments to confirm two key questions: First, does the molecular signature of covalent KRAS G12C inhibitors end up on the cell surface? Second, would this modified protein actually fit into the MHC complex, which presents antigens on the cell surface for T cells to recognize?
The answers were yes and yes.
Figuring out that the drugs can generate unique peptides downstream that can then show up on cell surfaces, the scientists believe, presents a nice way out in the often elusive search for tumor antigens. And it’s only possible once drugmakers came up with compounds that reliably bind to KRAS G12C mutations.
“It was always there sort of on the whiteboard, but very hard to implement until we had a very good molecule and then that served as the basis for the antibody selection,” Shokat said.
Often, Craik added, the difference between an antigen on a cancer cell and a protein on a healthy cell is simply too small.
“It’s just not enough to grab a hold of,” he added. “It’s like trying to climb a rock wall and just having a little bit to grab a hold of. You know, a hapten, a small molecule going and making something really big to grab a hold of — that’s when it took off.”
Rohweder then got to work fishing for antibodies that can unleash an immune response against those cancer cells, using the molecular tag conferred by KRAS G12C covalent binding. Specifically, he would need to find an antibody that binds to the peptide only when it’s presented in the MHC complex, and not to the drug while it’s floating in serum (which could lead to side effects).
He ultimately landed on a bispecific T cell engager, popularized by Amgen as BiTE. In cell lines, it proved highly effective in killing cancer — even those cells that are resistant to KRAS G12C inhibition.
While he also looked into traditional IgG antibodies, Rohweder said he found the BiTE to be superior.
“So in that case, it was empirical,” Rohweder said. “We’re also certainly interested in CAR-T cells and other modalities. But the way I think we view it is once you have the right antibody, that you have a lot of options with how you implement it.”
The researchers had mainly worked with AR-S1620, the KRAS drug first discovered by Shokat spinout Wellspring Biosciences, because it was also the most advanced candidate when they first started the project. But they also managed to apply the same method in generating an antibody against a peptide triggered by sotorasib — tucked in at the very end of the paper to underscore the promise of their tech.
Importantly, in this setting, the KRAS inhibitor can also serve as an off-switch for the antibody if the immune response becomes too much. Take the patient off the drug, and the T cells should theoretically lose their trigger.
The hope is that the approach could overcome the current limitations of KRAS drugs. While response rates in lung cancer have been encouraging, the long-term effects remain limited, and in colon cancer, responses have been minimal. Efforts to bring in immunotherapies by combining KRAS drugs with PD-(L)1 inhibitors have produced mixed data at best.
Pamela Munster
“Resistance can develop pretty quickly,” said Pamela Munster, director of UCSF’s Early Phase Clinical Trials Unit. “So there is the primary resistance of tumors — we give a KRAS inhibitor, the patient’s tumors never respond. And then those patients who respond to the KRAS inhibitors, and then within a few months, the tumor progresses, so that’s acquired resistance.”
Munster believes the discrepancies may be attributable to how different cancer types have different drivers. She will be leading the early clinical work on Hap10Bio’s programs, which she hopes will prove a “broader application as it’s bringing in potentially a cooperative partnership with other pathways.”
Bringing in the immune pathway because the way oncogenes work, Shokat posits, “inhibiting 90% of the signal of a KRAS tumor is probably not even enough.”
What bolsters Shokat’s confidence in the approach are emerging research papers from the past year or so that shed light on the mechanisms of resistance to Amgen’s sotorasib (Lumakras) and Mirati’s adagrasib.
“We had always assumed, I think, like many people in the field, that a covalent cysteine-targeted drug would come back with mutation of the cysteine — away. This is what happens in the BTK cysteine-targeted drug ibrutinib,” he said. “But all the G12C drug papers of resistance showed that you get side, other mutations in the pathway that sort of allows you to bypass the inhibition of the G12C drug. But the G12C mutation stays there. That was a shock, I think to everybody. […] But then you remember, the approach we have, as long as we have a G12C in that cell, we can put a drug on it, and then it’ll go up to the surface and then we can still identify that cell.”
Still in early stages, Hap10Bio plans to first pursue the indications where KRAS inhibitors have already been approved — specifically enrolling patients who progress despite KRAS therapy or relapse. It’s in talks with potential partners to discuss.
The company may eventually go beyond KRAS as the same approach can be applied to other cancer types that are amenable to covalent inhibition, such as tumors with p53 mutations.
“That covalency opens up a broader platform opportunity,” said Daniel Green, entrepreneur-in-residence at UCSF who will serve as Hap10Bio’s CEO.
For Shokat, it’s all about building on what he started.
My dream is that, you know, any patient that comes in and gets a G12C diagnosis that we could leverage all the therapies that are selected and on target the first time. Because once you give a patient the chance to get resistance, and then you’re dealing with resistance, you’ve already changed so much. It’s like the way we treat with antivirals — we give triple combination when we can. We give it upfront. You can drive infection out. That’s what we’d love to do with cancer. I think in order to get here, we need to bring in the immune system, as well as targeted therapy. This to me it seems like an ideal combo.
