Novel anti-CKAP4 antibodies bring hope for pancreatic cancer treatment

Pancreatic cancer is an aggressive disease for which there are few treatments. Fortunately, researchers are working hard to improve treatment options, and Japanese researchers recently revealed a promising discovery.

In a study published this month in The science of cancerResearchers at Osaka University have developed an “anti-cytoskeleton-associated protein 4 (anti-CKAP4) antibody.” This antibody blocks another protein, Dickkopf 1 (DKK1), from activating the DKK1–CKAP4 pathway, an important pathway that drives the growth and proliferation of cancer cells.

First, some background: CKAP4 is a cellular receptor, a structure on the outside of cells that can be activated by a specific protein. In this case, CKAP4 is activated by DKK1 to promote tumor growth. Elevated levels of DKK1 and CKAP4 in patients typically signal malignant transformation and poor prognosis. The research team therefore identified the DKK1–CKAP4 pathway as a target for novel therapeutic agents.

“We started with a recombinant mouse antibody. Our challenge was to develop a humanized form of this antibody that could produce the same effect as that obtained in mouse models and be used safely in humans,” explains the study’s lead author, Ryota Sada.

To do this, the researchers first confirmed that the recombinant anti-CKAP4 antibody inhibited DKK1–CKAP4 signaling and tumor formation in laboratory mice that had received human tumor cell transplants. They then used the recombinant antibody as a basis to develop the humanized antibody: Hv1Lt1.

They found that Hv1Lt1 was able to bind to CKAP4 even more effectively than the original antibody; moreover, Hv1Lt1 inhibited sphere formation, which is a measure of the ability of cancer stem cells to multiply into spherical-shaped colonies.

“After developing the humanized antibody, we tested it in several pancreatic mouse models, and the results were very promising,” said Akira Kikuchi, lead author of the study.

The researchers found that Hv1Lt1 suppressed tumor formation in mice that received either mouse or human pancreatic cancer transplants. Hv1Lt1 also helped modulate antitumor immune responses. Additionally, the researchers tested the response of mouse models receiving a combination of Hv1Lt1 and chemotherapy drugs and found that the combination treatment worked better than the drugs alone.

Another advantage of antibody-drug combinations is that they may help overcome the problem of chemoresistance by inhibiting the AKT (protein kinase B) pathway, which is typically activated by chemotherapy drugs. Using Hv1Lt1 in combination with chemotherapy could also reduce chemotherapy doses and resulting toxicity.

Overall, the researchers’ exciting findings pave the way for further research into humanized antibodies, with real hopes of improving the prognosis of patients with one of the deadliest cancers.