Humanizing Monoclonal Antibodies for Mucormycosis Treatment

Researchers have developed VX-01, a humanized monoclonal antibody designed to target mucormycosis, a severe fungal infection predominantly affecting immunocompromised individuals. VX-01 enhances the host's immune response and prevents fungal angioinvasion, offering a promising adjunctive treatment for this often fatal disease.

Mucormycosis, caused by Mucorales fungi, poses significant risks, especially to those with weakened immune systems. In the second part of our conversation with researcher Ashraf S. Ibrahim, PhD, senior investigator at the Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, he discusses over 20 years of research on mucormycosis, focusing on a key cell surface protein that facilitates the organism's aggressive tissue invasion.

“Basically, what we did is we've done a lot of work, and this is really the result of more than 20 years of research at the bench side trying to understand how the infection happens. So we've identified a cell surface protein that is expressed on the cell surface of the spores and the hyphae form of the organism. So you inhale the organism as spores. But what happens is they basically start germinating, forming hyphae. And that hyphae is really extremely aggressive in invading tissues, including blood vessels.”

The research identified a 16-amino acid peptide within this protein, which, when targeted with antibodies, could potentially block the organism's binding to mammalian cells.

“We've identified a protein called a spore coating protein. These proteins are professional invasins. In other words, their task is for the hyphae and the spores to bind the host cells, mammalian cells, human cells, and allow the organism to enter into the cell, embedding it and continuing to invade,” Ibrahim explains. “Within the protein itself, we've identified a 16-amino acid peptide that is highly immunogenic, surface exposed, and really resides in the binding facet of the spore coating protein to its receptor. The idea was to raise antibodies against that 16-amino acid peptide and see whether we can block the ability of the protein binding to its receptor, and as a result, prevent the organism from binding to the mammalian cell.”

Animal studies demonstrated efficacy, particularly when the antibody was combined with antifungal drugs.

“So in animal studies, we see actually very good efficacy of the antibody by itself given to mice. But then when you combine it with antifungals, the synergy is enormous. It's much better than either the antibody or the antifungal drug alone,” Ibrahim says.

However, the development of VX-01 faced challenges, particularly in the transition from murine to human antibodies.

“The difficulty was taking a mouse-derived monoclonal antibody and trying to give it to humans. In order for us to do this, we have to humanize it, because you can't give a mouse antibody to a human. One of two things would happen: either the antibody would be recognized as a foreign component and get destroyed by the human immune system, or you would have a severe allergic reaction, potentially leading to anaphylactic shock that might kill the patient,” Ibrahim notes.

Advances in humanization allowed for successful back mutations, improving the antibody's binding capability tenfold.

“We've done the humanization, and when we did this full humanization, we lost the activity of the antibody. It was no longer able to bind to the target protein. We had to go back and do back mutations—changing certain amino acids from the human frame back into the mouse frame. And we were able to do this with around 10 amino acids, which is acceptable by the FDA,” Ibrahim explains. “And then, all of a sudden, we not only restored the binding capability of the antibody, but we actually improved it by tenfold. We went from approximately 50 nanomolar to five nanomolar, which is really acceptable by the FDA for therapeutic antibodies.”

Production posed another challenge, particularly with Chinese hamster ovary (CHO) cells, the standard cell line for producing biologics.

“The only problem we've had in humanization was really production in CHO cells, which is the standard cell line for producing therapeutics. We were able to produce commercially viable quantities of approximately two to three grams per liter. What also helps us is that we don't have to go into high amounts of production because we don't have to give a huge amount of the antibody to see efficacy,” Ibrahim says. “So we see efficacy, on the basis of a human being, at approximately 100 milligrams total, which is considered to be a very low dose.”

Part 1 of our interview: VX-01 Monoclonal Antibody Targets Mucormycosis by Blocking Angioinvasion

Reference

Gu Y, Singh S, Alqarihi A, et al. A humanized antibody against mucormycosis targets angioinvasion and augments the host immune response. Sci Transl Med. 2025;17(789):eads7369. doi:10.1126/scitranslmed.ads7369