Antibody drug conjugates: BiVictriX drives a new era in cancer medicine

Photo/Anastasiia Slynko

The first-ever antibody-drug conjugate (ADC) to be approved, gemtuzumab ozogamicin, raised hope for a new class of drugs to treat cancer. But the drug was then withdrawn following a black box warning after patients experienced adverse side effects, and there had been fatalities. But this didn’t discourage biopharmas looking to create safer alternatives from expediting research in the field. And in the race to develop well-tolerated cancer therapies, BiVictriX is pulling ahead in developing a targeted treatment for acute myeloid leukemia (AML). 

AML is a type of blood cancer that is estimated to affect over 20,000 people this year, in the U.S. alone. Making up about 1% of all cancers, AML originates from immature white blood cells. Because they are not fully developed cells, they do not possess properties that protect the body from infections. As these cells increase in an unregulated manner, the number of red blood cells and platelets decline, leading to some of the symptoms of leukemia such as fatigue, increased risk of infections, easily bruised skin and joint pain. While the exact cause of AML – as with other forms of cancers – isn’t entirely clear, an elevated risk of AML comes with increased exposure to radiation, being diagnosed with certain blood disorders as well as having previously undergone cancer treatments.

Currently, chemotherapies and stem cell transplants are regarded as standards of care, along with radiation therapy, but ADCs are now making a comeback. ADCs comprise a monoclonal antibody – which binds to the cancer protein in a cell – attached to a linker, which delivers the anticancer drug once the antibody latches on to the cancer cell. So, unlike conventional chemotherapies, these drugs tend to spare healthy cells, and are a more targeted approach to treating cancer. At present, 14 ADCs are commercially available, a flurry of which were granted approval in the past few years. 

Based in Cheshire, in the U.K., BiVictriX’s lead programme for AML is BVX001, a bispecific ADC that targets a combination of antigens, CD7 and CD33. These antigens are found on leukemia cells, and in nearly a quarter of patients with AML. 

How is BiVictriX addressing the shortcomings of ADCs?

“So, we’re designing this drug to retain all of the potency benefits of an ADC approach, but with much more cancer selectivity. And one of the biggest problems in AML is significant toxicities, particularly around the bone marrow, leading to neutropenia and neutropenic sepsis, which is actually deadly. And in fact, it is one of the leading causes of death for patients with acute myeloid leukemia,” said Tiffany Thorn, CEO of BiVictriX. “With BVX001, our lead therapeutic, we have designed a drug that is very potent to the targeted cancer cells, but does not seem to cause any bone marrow toxicity in the assays that we’ve currently looked at.”

A frequent side effect of chemotherapy, bone marrow toxicity occurs when fewer immune cells are produced by the bone marrow. This can result in neutropenia – a reduction in neutrophils, which are cells that fight infection – making the body more prone to infections, as well as neutropenic sepsis – a complication of neutropenia – which can be lethal. 

In preclinical studies, BiVictriX demonstrated promising results, which, if reproduced in clinical trials could be revolutionary, Thorn expressed. With the help of mice models that had human AML cell lines, a solid tumor was grown on the back of the mice. Then, they were dosed with the drug candidate BVX001, which saw a 93% regression in the first model. In the second model, where the tumor was grown to a much larger extent, a 97% decrease in tumor size was observed at the end of 28 days. 

“We’ve actually made our lives a lot harder to start off with, by choosing this very problematic cell line. But we’ve done that on purpose to really show the benefits of this drug,” said Thorn, who added that the results were “highly statistically significant.”

The promise of a targeted therapy

In addition to the preclinical trial, the drug underwent a safety study earlier this year. BVX001 was tested on a humanized mouse model, wherein the human immune system is replicated. This study compared BVX001 to gemtuzumab ozogamicin, sold under the brand name Mylotarg, which upon being pulled from the market in 2010, was reapproved, but at a lower dose in 2017, owing to a lack of any notable breakthrough in AML research. The study revealed that BVX001 did not cause bone marrow toxicity or neutropenia, deeming it to be safe.

“We’re not aware of anybody else that’s working on this particular concept – so, we designed the ADC so that they’re able to truly discriminate cancer cells from healthy cells. So basically, the drug only binds to and releases the payload in the cancer cells,” said Thorn.

This way, it ensures that the payload does not get released externally in the plasma or in healthy cells that may express a similar antigen. Specifically designed for patients in their 60s or older, who are not considered to be fit for intensive therapy, the drug could provide an effective and curative option to those patients that require a therapy that doesn’t carry the same side effects as many of the other drugs on the market, according to Thorn.

“If the preclinical data does translate in the clinic, I think this would be a very, very significant drug and particularly for those patients that can’t withstand other intensive therapies,” said Thorn. “Most of the drugs on the AML market are small molecule drugs, which target particular molecular mechanisms that lead to the disease. Whereas as an ADC company, we basically target the cells and we deliver a really potent chemotherapy agent into those cancer cells and kill them from the inside out.”

Moreover, as the drug targets two antigens on the surface of leukemia cells, which specifically label the cells, it only internalizes when those antigens are present. As a result, it leaves healthy cells unscathed.

The idea behind the technology spurred when Thorn trained as a clinical immunologist in the National Health Service (NHS) in the U.K. “I think that’s where that’s given me that unique insight… These cancer cells, if you look at the patterns on the surface, they actually do have these ‘barcodes’ available, which allows you to pinpoint a cancer cell from another healthy cell in a sample,” said Thorn, who went on to found BiVictriX in 2017 upon receiving its initial investment to further enhance its pipeline.

Could the platform treat various kinds of cancers?

As the mechanism behind BVX001 can be employed to treat other kinds of cancer, the company’s Bi-Cygni ADC platform has been key to developing two other drug candidates as well, BVX002 and BVX003, for the treatment of ovarian cancer, bladder cancer and solid tumors. Both candidates are presently in their development stages, and will be put through preclinical trials soon.

With an aim to showcase BVX001’s clinical benefit against AML, BiVictriX is looking to eventually partner to advance in ADC development. Having raised £2 million ($2.58 million) in a conditional fundraise this month, the company is one step closer to bringing its ADC technology to the market.

“I really, really believe in this technique, mainly because it’s been used for diagnostic purposes for so long. So it’s been used for over 20 years in the U.K., in Europe and the U.S. to diagnose people with certain types of cancer. And I was just quite surprised that nobody had ever trialled this from a therapeutic point of view to try and reduce side effects in the clinic. So hopefully, our preclinical data will translate well into the clinic. And we’ll be able to produce these drugs without the significant side effects that we currently see.”

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