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New class of drug conjugate
CAMBRIDGE, U.K.—The Avacta Group, based in the United Kingdom, pursues novel cancer immunotherapies utilizing two specific and proprietary tools: their Affimer reagents, and their pre|CISION tumor-targeted chemotherapy options. In combining these two resources, they recently shared promising proof-of-concept data indicating that a novel class of drug conjugate—the tumor microenvironment activated drug conjugates (TMAC)—has overtaken Pfizer’s avelumab injection (Bavencio) as the best current option for some cancers.
Affimers are substantially smaller than antibodies, which gives them greater potential for increased tissue penetration, particularly in fibrotic tissue or tissue with compromised bloodflow. Because nearly 20 percent of cancers are linked to chronic inflammation-related fibrosis (including pancreatic, liver, gastric, esophageal, head/neck, colon and cervical), Avacta researchers posited that Affimers could provide unique advantages to traditional antibodies.
“Traditional antibody-drug conjugates (ADCs) require internalization by the target cell in order that the toxin payload they carried be released by enzymes in the lysosome of that cell,” according to Matt Vincent, Avacta’s vice president of therapeutics, and Amrik Basran, Avacta’s chief scientific officer. “However, while we have programs with partners ... that utilize Affimers in place of antibodies for more traditional internalization ADC-like approaches, most of our own internal oncology Affimer pipeline was focused on targets that are not readily internalized, so not useful with the ordinary cathepsin-sensitive linkers used for ADCs.”
While theorizing about ways to employ their existing internal Affimer pipeline, Avacta invented the concept of TMACs, a new form of cancer immunotherapy, co-invented with the Tufts University School of Medicine. As per Avacta’s website, TMACs combine Affimers with chemotherapies in a single drug using a linker that is designed to only release the chemotherapy in the tumor microenvironment. This allows chemotherapies that are too potent to be given to patients systemically to be combined with Affimer immune-checkpoint therapies.
According to Vincent and Basran, “This mechanism overcomes the need to target an internalizing cancer marker, as with conventional antibody-drug conjugates, and allows extremely potent chemotherapies to be combined with Affimer immune-checkpoint therapies. Combining pre|CISION technology with the Affimer platform is enabling Avacta to build a pipeline of novel and safe cancer therapies applicable to a broader range of cancer patients, including those who do not respond to existing immunotherapies.”
The resulting conjugate, AVA04-VbP, combines an Affimer checkpoint inhibitor with an I-DASH chemotherapy, targeting linking agents found only in the tumor with small-molecule inhibitors that are activators of innate immunity. This results in a highly localized inflammatory event that is synergistic with the Affimer checkpoint inhibitor, without the common toxicity associated with I-DASH inhibitors alone. As stated in a press release, this induces a highly pro-inflammatory cell death, which in turn stimulates an immune response in the tumor, which is supported by the Affimer PD-L1/PD-1 signaling pathway blockade.
Vincent and Basran point out that the chemotherapy release within the tumor is activated by an extracellular enzyme called fibroblast activation protein (FAP). While other companies are exploring ways to use antibodies to target drugs to the tumor which may bind with FAP, they say Avacta's particular application is unique.
“We knew that FAP was a post-proline cleaving enzyme, and through a relationship with Bill Bachovchin at Tufts Medical School we set up a collaboration to generate drug conjugates that could only be released by FAP cleavage of the linker,” the pair told DDNews. “In the conjugated form, the drug moiety is inert. Upon FAP cleavage in the tumor, the drug is released in its most active form. At the same time, the PDL1 inhibitory Affimer or antibody continues to function as a checkpoint inhibitor. Put simply, the [combination] induces a potent immune signal in the tumor while the Affimer/antibody checkpoint inhibitor makes sure that the immune response is not shutdown by PD-L1 expression in the tumor upon T cell infiltration. Our initial results have been really exciting, showing that even in CT26 tumor models (a model in which PD-L1 inhibitors do not perform well) our TMAC constructs have been able to produce full regression.”
Proof of concept was established through a mouse syngeneic tumor model, which indicated improved performance over the already established anti-PD-L1 immunotherapy Bavencio. As their reported data indicates, animals treated with AVA04-VbP showed a significant slowing in tumor growth, with a considerably higher level of the released I-DASH present in the tumors compared with very low levels in the blood, indicating that healthy tissues are less exposed to the highly toxic weapon.
Avacta researchers are very optimistic about their next steps. They expect that the FAP-activated TMACS in general will be useful in solid tumors having elevated levels of expression of FAP, which includes a wide range of solid tumors. Pancreatic tumors in particular are of interest, as those tumors tend to have the highest elevated levels of FAP expression, as well as often being marked by fibrosis.
“Beyond FAP expression,” comments Vincent, “the utility of the TMAC construct will also depend on the warhead chosen. And we have a range of possibilities in addition to innate immune activators, including agents which promote immune infiltration by breaking down the tumor stroma, as another example. Beyond Affimer and antibodies targeting PD-L1 and other checkpoint programs monomerically, we are exploring the ability to generate TMACs utilizing bispecifics. Accordingly, in a single molecule we may be able to hit three or more different pathways which collectively help to create a productive and sustained antitumor response.”