Results from a preclinical toxicity evaluation study with BVX001, a novel antibody-drug conjugates (ADC) being developed by UK-based BiVictriX Therapeutics, showed positive in vivo data when compared to gemtuzumab ozogamicin (Mylotarg™; Pfizer).

Gemtuzumab ozogamicin, an ADC consisting of a monoclonal antibody targeting CD33+ expressing cells linked to a cytotoxic derivative of calicheamicin, is the only approved ADC indicated for the treatment of patients diagnosed with acute myeloid leukemia (AML).[1]

One of the significant toxicities of gemtuzumab ozogamicin is the reduction in normal neutrophil counts in patients with AML. Neutrophils are a form of immune cell and a reduction in the number of these cells heightens the risk of neutropenia, low blood count, severe infections and sepsis, which can be fatal. This is a major concern in the treatment of patients with AML.

AML is the most common type of acute leukemia in adults, for which more targeted, less toxic treatments are needed.

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Well-tolerated
BVX001 was reported to be well-tolerated and showed a highly favorable safety profile across two doses of BVX001 (0.3 mg/kg and 3 mg/kg), compared with the reported maximum tolerated dose of gemtuzumab ozogamicin (0.3 mg/kg) in a CD34-boosted humanised murine model. The results showed that:

  • The proportion of healthy human CD33+ myeloid cells in the bone marrow was significantly lower with gemtuzumab ozogamicin compared to BVX001 at both an equivalent dose to gemtuzumab ozogamicin (0.3mg/kg) and a 10-fold higher dose (3mg/kg), at seven- and fourteen-days post-injection.
  • The total number of healthy neutrophils and total healthy leukocytes, types of specialised immune cells, were significantly lower with gemtuzumab ozogamicin compared to the equivalent dose of BVX001, at fourteen days post-injection.
  • The total number of healthy human CD33+ cells was significantly lower with gemtuzumab ozogamicin compared to the vehicle control seven days post-injection.

These results model commonly reported toxicities of gemtuzumab ozogamicin in clinical practice.

Other observed effects with gemtuzumab ozogamicin included a non-statistical lower level of healthy early bone marrow progenitor cells at day fourteen post injection, compared to both doses of BVX001. A non-statistical higher proportion of CD7+ cells among CD3+ T cells in blood at day three post injection was reported with gemtuzumab ozogamicin , compared to BVX001 and the control vehicle

“Receiving these positive preclinical safety results, soon after identifying a development lead for BVX001, reinforces the superior cancer selectivity of our Bi-Cygni® approach – designing drugs with reduced toxicity on normal cells,” noted Tiffany Thorn, Chief Executive Officer of BiVictriX Therapeutics.

Bypassing limitations
BiVictriX’s proprietary bispecific Bi-Cygni® therapeutic approach bypasses a known limitation of targeting a single protein expressed on both healthy and cancer cells by selectively targeting “twin antigen fingerprints” which are uniquely expressed on cancer cells.

The company’s proprietary library of “twin antigen fingerprints” enables these fingerprints to be selectively targeted while leaving healthy cells alone. Through this program, researchers can selectively target the cancer specific twin antigen fingerprint, CD7+CD33+, which is found to be expressed on AML cancer cells, but largely absent from healthy cells throughout the body.

“These findings move us another step closer to the clinic and provide further evidence that our first-in-class platform offers the potential to deliver the next generation of highly selective, anti-cancer therapies,” she added.

“Generating data that demonstrates BVX001 was well-tolerated in this in vivo model and showed reduced off-target effects, when compared to the only approved ADC drug addressing AML, puts us in a strong position to break into the market with the goal to offer a novel, game-changing bispecific treatment with better efficacy and improved safety for patients,” Thorn concluded.

Building on the initial promising in vivo efficacy data seen with BVX001, BiVictriX has now successfully demonstrated, in a head-to-head comparison with a commercially available ADC, that the Bi-Cygni® ADC approach offers the potential to overcome some of the drug-induced life-threatening side effects linked to bone marrow toxicity that have been reported with ADCs in the clinic, such as gemtuzumab ozogamicin.

The results from this in vivo toxicity evaluation study will be submitted for publication and will be presented at an upcoming scientific conference.

Highlights of prescribing information
Gemtuzumab ozogamicin (Mylotarg™; Pfizer)[Prescribing information]

Reference
[1] Baron J, Wang ES. Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia. Expert Rev Clin Pharmacol. 2018 Jun;11(6):549-559. doi: 10.1080/17512433.2018.1478725. Epub 2018 Jun 11. PMID: 29787320; PMCID: PMC6661897.

Featured image Photo by National Cancer Institute on Unsplash

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