Gene therapies for sickle cell disease could be game-changing for patients, but they come at a cost (and not just the estimated $2 million per patient): The process of pre-treatment conditioning, where high-dose chemotherapy is used to clear out a patient’s blood stem cells in the bone marrow to make room for new ones, can cause infertility.
Now, researchers from the U.S. National Institutes of Health (NIH) have shown that replacing the chemo with an antibody-drug conjugate (ADC) could eliminate that risk. In a paper published Oct. 12 in Nature Communications, they describe how a drug called CD117-ADC successfully cleared blood stem cells from male and female primates and allowed engraftment of new stem cells that produced healthy fetal hemoglobin—a key correction for curing sickle cell disease—while also conserving the animals’ fertility.
“These data demonstrate that CD117-ADC conditioning can allow for not only the engraftment of [blood stem cells] but also the maintenance of fertility, even when both the male and female underwent conditioning and transplantation,” the researchers wrote in the paper. “Fertility preservation should expand the option of [blood stem cell] gene therapy, since infertility is a major reason why young patients do not select it.”
Chemotherapy for pre-treatment conditioning usually takes the form of busulfan, under the trade names Busulfex or Myleran. The drug is also used to treat leukemia and is used for conditioning ahead of a bone marrow transplant, the only other curative treatment for sickle cell disease. As an alkylating agent, it’s more likely than other types of chemo to damage sperm development and can cause ovarian failure.
Over the past several years, researchers have increasingly looked to ADCs as a potential alternative to traditional chemo. Combining an antibody with a chemo agent, some ADCs are already being used in oncology. By targeting the antibody to bind with an antigen present on tumor cells, ADCs aim to limit the effects of chemo by avoiding healthy tissue and unwanted off-target effects.
The new therapy developed by the NIH team works essentially the same way. CD117-ADC is a combination of an antibody aimed at the enzyme CD117—a protein expressed mainly by bone marrow stem cells—and a chemo drug in a class of alkylating agents called pyrrolobenzodiazepines, or PBDs. PBDs are used in other types of ADCs as well, such as in ADC Therapeutics’ FDA-approved anti-lymphoma agent Zynlonta. “Importantly, this ADC is engineered to enable rapid clearance, ensuring full wash-out prior to implementation of transplantation,” the researchers said in their paper.
The scientists first tested CD117-ADC on three rhesus monkeys, which were compared to three primates of the same species that underwent standard conditioning with busulfan. One IV administration of the ADC depleted bone marrow stem cells to the same degree as the chemo agent, with no serious side effects. The drug was not toxic to other types of cells that express smaller amounts of CD117, such as the thymus, mast cells and melanocytes in the skin, nor did it appear to be cytotoxic to differentiated blood cells in serum samples from the animals.
Next, the researchers tested whether CD117-ADC could induce marrow depletion and allow for the subsequent engraftment of new blood stem cells without toxicity. Following a single dose of the drug, they infused genetically modified blood stem cells. They were able to engraft the same amount of cells following CD117-ADC conditioning as they did when they used busulfan, and the cells produced healthy fetal hemoglobin—a good sign that the treatment could successfully treat sickle cell disease.
Apart from transient increases in liver enzymes and some unexpected, temporary changes in blood cell counts, CD117-ADC was well tolerated by the primates. But what about its effects on fertility? The female monkeys continued to menstruate following treatment, suggesting that ovulation remained intact. And when six of them—four females and two males—were transferred to a breeding colony, two of the females gave birth. Both males successfully impregnated females, including one of the female primates that received the treatment.
While the researchers currently don’t have plans to perform clinical trials, they “are hopeful that an industry partner will take this up,” NIH scientists and study leads John Tisdale, M.D., and Naoya Uchida, M.D., Ph.D., told Fierce Biotech Research in an email.