A target-agnostic search has yielded a patient-derived antibody that activated the innate immune system, researchers from Atreca and Stanford University reported in the May 4,2022, issue of the Proceedings of the National Academy of Sciences.
The antibody they described, ATRC-101, is now in a phase I trial in patients with advanced solid tumors.
The method used to identify it could yield multiple novel targets by looking at which tumor antigens the immune system of cancer patients that are mounting an immune response have picked.
The method, Tito Serafini told BioWorld Science, starts with screening patient samples.
Serafini, who is co-founder and chief strategy officer of Atrca, said that "we have samples, and we run our own noninterventional studies to correct the right samples," which by now number 1,700 from 500 donors in 35 solid tumor types.
The screening system, which was developed by Serafini and his Atreca co-founder and PNAS co-author William Robinson, focuses on a type of B cell called plasmablasts, plasma cell precursors that produce antibodies but can also still proliferate.
Plasmablasts "are pretty rare, even in patients having an immune response," Serafini explained.
And during an active immune response, they provide a readout of what the immune system is going after.
"So instead of going through memory B cells and looking, essentially, for a needle in a haystack made of needles.... [we] only need to look at one to two thousand plasmablasts to get a pretty good idea of what the immune system is doing at that moment."
Any promising antibodies are then tested to see whether they bind to tumors from other patients.
"And if the answer is yes, we have what we call a hit antibody that can be used potentially to treat large numbers of patients," Serafini said.
The screening system is not limited to identifying antitumor antibodies – Robinson's lab at Stanford University recently used it to show that autoantibodies in multiple sclerosis can arise from an immune response to Epstein-Barr virus.
The majority of the antibodies that Atreca's team has identified to date has needed weaponization, for example by turning them into antibody-drug conjugates (ADCs).
ATRC-101, though, induced an antitumor immune response by myeloid cells of the innate immune system.
The team showed that ATRC-101 targets an RNA binding protein complexed to its RNA, which it delivers to myeloid cells.
This activates myeloid cells, which wakes up the innate and ultimately, the adaptive immune system. The myeloid cells produce chemokines and cytokines, followed by macrophage and dendritic cell activation and finally, T-cell mobilization.
Tumor cells can evade antibodies by losing the expression of the antibody's target. Serafini said that there are ways to look for plasmablast-produced antibodies over time, which would suggest that the antibody target in question is persistent.
But also, persistence is not necessarily a prerequisite for success.
ATRC-101, for example, "is acting like a lit match," Serafini said. "You take 101, you apply it to the tumor, and light up an immune response. And at that point, you don't need the dosing anymore."
Nor are only antibodies from patients who have mounted a successful antitumor immune response useful.
"We're going into the patients that have an immune response," Serafini said, but "there are no magic antibodies in a particular patient."