Bispecific antibodies, as the name suggests, simultaneously target 2 or more tumor antigens on the same or separate cells to disrupt cancer development or progression. Others engage and tether cancer cells and immune cells together to increase cancer-cell destruction.

No matter the strategy researchers take, however, interest in these bioengineered antibodies has been rekindled by the striking success seen in the treatment of some cancers with immunotherapy — notably, checkpoint inhibitors and chimeric antigen receptor T-cell (CAR-T) therapy — in the past few years.

“Bispecific antibodies were stalled for a bit, but in this new era of immunotherapy, there’s definitely renewed interest,” said Nikhil Munshi, MD, a medical oncologist at Dana Farber Cancer Institute and director of basic and correlative science at the Jerome Lipper Multiple Myeloma Center in Boston, Massachusetts. “And, we have newer, more modern methodologies that have propelled the field forward.”

An estimated 50 clinical trials using bispecific antibodies for various malignancies are now underway, while biotechnology companies and academic labs purportedly have hundreds of different products in development and awaiting testing.¹

Still, the US Food and Drug Administration (FDA) has approved only 1 bispecific antibody with a cancer indication so far, underscoring the need for further research, before these targeted biologics can emerge as viable and less costly alternatives to other types of immunotherapy that are highly tailored to an individual’s cancer.

In July 2017, the FDA approved Amgen’s bispecific antibody, blinatumomab (Blincyto) for acute lymphoblastic leukemia (ALL) in adults and children with advanced disease.² Blinatumomab targets and binds 2 proteins, one, CD19, that is found on the surface of B-lineage cells and the other, CD3, that is found on T cells — essentially bringing the 2 in close enough proximity that T cells better recognize leukemic cells to kill them.

Other investigators are using similar tacks in creating these dual-targeting agents.

Researchers at The Ohio State University Comprehensive Cancer Center in Columbus, for example, used an approach comparable to blinatumomab in a humanized mouse model for multiple myeloma, according to Ilan Zipkin, PhD, a vice president at the Parker Institute for Cancer Immunotherapy in San Francisco, California. But the investigators extended the approved drug’s approach, he says, by tethering a common tumor antigen in this cancer, CS1, to a receptor, NKG2D, expressed on several types of immune system cells that kill.

Dr Zipkin wrote in an email that the Ohio researchers “are showing activity with a bispecific that promotes several different cell types to kill the myeloma cells,” including, importantly, natural killer cells. Results of that study were among those highlighted at the American Association for Cancer Research Annual Meeting in Chicago, Illinois, earlier this year.³

In multiple myeloma, CS1 is considered a well-defined antigen, which investigators already are targeting with CAR-T therapy, according to Dr Munshi. “But this group put it together with NKG2D, an interesting molecule, which is scientifically intriguing,” he says. “They showed a good response.”

Nevertheless, for this and other bispecific antibodies to work best in patients, Dr Munshi said there is a prerequisite: a functional immune system must be present. CAR-T therapy has a clear advantage over bispecific antibodies right now, he explained, because “you can overcome some of the immune-suppressive environment” that occurs. Still, given the prohibitive costs of CAR-T’s customized approach, Dr Munshi and others believe bispecific antibodies could provide an economical alternative for patients in the future, broadening access to treatment.

Michael Verneris, MD, director of bone marrow transplant and cellular therapy at Children’s Hospital in Denver, Colorado, also sees an evolving role for these next-generation designer antibodies. Although the need for intact immunity and a lack of persistent therapeutic effect pose barriers right now, he says, bispecific antibodies have considerable upside, as well.

“These are modular, relatively small molecules that can be quick to produce,” he said. “If ‘A’ and ‘B’ don’t work, you can keep on mixing and matching until you can create whatever you want.” One obvious advantage to patients is that if complications arise, they can be addressed quickly, he said.

“The great hope is that these will be in the deck of options for patients,” as an integral part of a multipronged strategy against cancer, Dr Verneris said.

Although no bispecific monoclonal antibodies in the first-line setting exist yet, he is confident that clinical trials in patients with early-stage cancers eventually will take place, when chemotherapy damage to their immune systems is not so extensive.

Dr Verneris said he has watched unlikely strategies in immuno-oncology gradually unfold successfully before, and the same could happen with bispecific antibodies. “It’s been hugely gratifying to see some of these ideas come raging forward.”

References

1. Krishnamurthy A, Jimeno A. Bispecific antibodies for cancer therapy: a review. Pharmacol Ther.2018;185:122-134.
2. FDA grants regular approval to blinatumomab and expands indication to include Philadelphia chromosome positive B-cell. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm566708.html. Updated July 12, 2017. Accessed August 20, 2018.
3. Chan, WK, Kang S, Youssef Y, et al. A CS1-NKG2D bispecific antibody collectively activates cytolytic immune cells against multiple myeloma. Cancer Immunol Res.2018;6(7):776-787.

Susan Jenks

August 22, 2018

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