Madrid. A group of researchers from Osaka University, Japan, developed a new antibody humanized
effective against pancreatic cancer in mouse models, according to a study published in the journal Cancer Science.
This is an antibody against cytoskeletal-associated protein four (antiCKAP4). The antibody prevents another protein, known as Dickkopf 1 (DKK1), from activating DKK1-CKAP4, an important pathway that stimulates the growth and proliferation of cancer cells.
CKAP4 is a cellular receptor with a structure on the outside 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 are often a sign of malignant transformation and poor prognosis. The research team thus identified the DKK1-CKAP4 pathway as a focal point for new therapeutic agents.
Transplanted human cells
We started with a recombinant mouse antibody. Our challenge is to develop a humanized form of this element that can achieve the same effect as that achieved in mouse models and be used safely in humans.
explains the study’s lead author, Ryota Sada.
The researchers first confirmed that the recombinant anti-CKAP4 inhibited DKK1-CKAP4 signaling and tumor formation in laboratory mice that had received transplants of malignant human cells. They then used the recombinant antibody as a basis to develop the humanized Hv1Lt1.
They found that the latter is able to bind to CKAP4 even more effectively than the original antibody. What’s more, Hv1Lt1 inhibited sphere formation, which is a measure of the ability of cancer stem cells to multiply into sphere-shaped colonies. After developing the humanized antibody, we tested it in several pancreatic mouse models and the results were very promising.
said Akira Kikuchi, co-author of the paper.
The researchers found that Hv1Lt1 suppressed tumor formation in mice that received transplants of pancreatic cancer from both human and mouse sources. Hv1Lt1 also helped modulate anti-tumor immune responses. In addition, the scientists tested the response of mouse models that received a combination of Hv1Lt1 and chemotherapy drugs and found that the combination treatment worked better than either drug alone.
Another advantage of antibody-drug combinations is that they can help overcome chemoresistance by inhibiting the AKT (protein kinase B) pathway, which is often activated by chemotherapy drugs.
The use of Hv1Lt1 with chemotherapy could also reduce chemotherapy doses and resulting toxicity.