Cancer Proteins Deep within Tumor Cells Targeted by Dimeric Antibodies

Researchers led by a team at Duke University School of Medicine have developed an approach to cancer treatment that they describe as more precise, long-lasting, and less toxic than current therapies. The new technology uses dimeric IgA (dIgA) antibodies to target and kill tumor-promoting molecules found deep within cancer cells that have long eluded existing treatment options, including IgA antibody therapy.

The team’s early experiments in mice with lung and colon cancer found that treatment using the antibodies resulted in notable reductions in tumor growth, and was associated with minimal side effects. “This is a proof-of-concept study, but the results are very promising,” said immunology researcher Jose Ramon Conejo-Garcia, MD, PhD, a Duke Science and Technology scholar in the Department of Integrative Immunobiology. “We believe that this treatment could be used to target a wide range of cancer mutations.”

Conejo-Garcia and colleagues reported on their studies in Immunology, in a paper titled “Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers.” In their paper the team concluded, “Our results provide a rationale for developing dIgA-based therapeutics to neutralize various intracellular antigens in human cancer and other diseases.”

“KRAS is considered the most common mutated oncogene driving human cancer,” the authors wrote. “KRAS mutations are particularly frequent in pancreatic, colorectal, non-small cell lung, and endometrial cancers,  which total more than 50,000 cases annually.” One KRAS mutation, KRAS G12D, (KRAS^G12D) is a known instigator of the deadliest cancers.

Existing cancer treatments may offer a double-edged sword, in that as well as killing cancer cells they can also wreak havoc on healthy cells. The authors’ newly reported study focused on harnessing a particular type of antibody called dimeric IgA (dIgA). While monomeric IgA is found in serum, at mucosal surfaces, IgA is predominately found as a dimer, and binds to the polymeric immunoglobulin receptor (PIGR) expressed on the surface of mucosal epithelial cells. This binding triggers a process called transcytosis, which transports the PIGR:antibody complex through the epithelial cell into the mucosal fluids. The team had previously shown that PIGR is expressed in some human cancers and allows transcytosis of dIgA through the tumor cells. For their newly reported work the researchers developed a recombinant dIgA that targets KRAS^G12D.

In vitro experiments showed that the recombinant, mutation-specific dIgA could bind to mutated KRAS^G12D in cancer cells, neutralizing it but also expelling it outside the tumor cell via transcytosis, stopping tumor growth. “Together, these results indicate that tumor cell-penetrating dIgA can indeed target specific mutations in KRAS inside tumor (e.g., ovarian cancer) cells, resulting in intracellular decreased levels and expelling the oncodriver outside the tumor cell, without obvious effects in KRAS unmutated epithelial cells,” they wrote.

When tested in mice, the KRAS^G12D-specific antibody was more effective at shrinking cancer tumors than current treatments in clinical testing. Small molecule treatments often struggle to reach certain cancer cells, have short-half lives, and can cause side effects.  “These experiments support the potential of tumor-cell-penetrating dIgA to specifically target mutated oncodrivers inside carcinoma cells in vivo,” the scientists stated.

In additional, the researchers reported similar results in vitro using an dIgA that targeted an intracellular cancer mutation, IDH1 R132H, found deep inside cancer cells.

According to researchers, IGA antibodies have the potential for use as targeted therapy against stubborn mutations driving common, aggressive cancers, particularly epithelial cancers such as ovarian, skin, colon, cervical, prostate, breast, and lung cancer. “Together with data from targeting KRAS-mutated lung tumors, these results support the potential of targeting carcinomas of multiple histological origins and different mutated oncodrivers, using antigen-specific dIgA,” the investigators stated. “Given that PIGR is expressed in most epithelial malignancies, but only at lower levels in non-epithelial cancers, this mechanism could be relevant for most human epithelial cancers. This should include recalcitrant tumors such as pancreatic or small cell lung cancers, which our data show quasi-universally express PIGR.”

“This is a new way of targeting tumor cells by using an antibody that is exquisitely specific for point mutations or molecules that are truly tumor specific,” said Conejo-Garcia. “By neutralizing them and ensuring these tumor-promoting molecules are expelled outside the cell, we can halt tumor growth.”

Scientists have struggled to target the mutated KRAS protein, but the new findings suggest the uniquely designed antibody can reach these intracellular molecules. The results suggest a strategy for developing future cancer treatments that are more tailored, reducing harm to healthy cells and improving patients’ quality of life. Researchers are refining the antibody to make it easier to produce and administer to patients, with the aim of eventually testing it in clinical trials.

Moreover, Conejo-Garcia noted, “The immune system is the only system in the body that has two key properties that make it ideal for cancer treatment: specificity and memory.” The immune system can specifically target tumor cells and it can also remember those cells to mount a more effective attack if the cancer returns.

While noting limitations of their studies, the authors suggest that future research should examine whether other commonly mutated oncogenes such as phosphatidylinositol 3-kinase (PI3K) or Ak strain transforming (AKT), or immunosuppressive intracellular pathways such as indoleamine 2,3-dioxygenase 1 (IDO), could be more effectively targeted using dIgA than with small-molecule inhibitors. “dIgA-mediated targeting, along or in combination with small molecules, could have substantial advantages, compared with small molecules: first, our results underscore the specificity of this approach,” they commented.

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