Bispecific Antibodies Wage a Two-Pronged Attack on Tumors

CURE, Immunotherapy Special Issue 2021,

BiTE therapy could lead to better ways to target the immune system, while minimizing the chance of resistance.

After Michael Herman received a diagnosis of high-risk multiple myeloma in 2013, he started a treatment journey that included several years of chemotherapy and the targeted drug Venclexta (venetoclax tablets), which is investigational for the disease and was designed for patients whose cancers have certain genetic abnormalities. The medicines worked well, but as is often the case with multiple myeloma, Herman’s cancer eventually returned.

In July 2019, Herman qualified for a clinical trial of teclistamab, an investigational drug that’s part of an emerging class of immunotherapy medicines known as bispecific antibodies. He traveled from his home in Galena, Maryland, to the University of Pennsylvania in Philadelphia to get the treatment: a weekly shot in the abdomen.

After just one dose of teclistamab, Herman’s cancer load dropped 99%. His disease is no longer detectable, and the study investigators have told him he can stay on the drug as long as it continues to be effective. In terms of side effects, Herman experiences some aches and pains, but says that it doesn’t affect him from getting around.

“When I was diagnosed, I was told my life expectancy was four years,” says Herman, 59, a retired corporate real estate manager. “This drug doubled that. It’s a wonderful thing.”

Teclistamab is one of several bispecific antibodies being developed to treat a range of cancers. Bispecific antibodies are designed to simultaneously bind two targets — a target on immune cells and another on tumor cells — pulling them together to unleash an immune attack against the cancerous cells. In the case of teclistamab, the two targets are an antigen called CD3 in the immune system’s T cells, and BCMA, which is an antigen that’s overexpressed in multiple myeloma.

Several other bispecific antibodies are under development to treat blood cancers and a wide range of solid tumor types, including cervical, gastric, brain and liver.

“The idea behind combination immune therapies, which include bispecific antibodies, is to find ways to better target the immune system from the get-go, to minimize the chance of resistance or improve the chance of getting a good response,” says Dr. Deborah Wong, an oncologist at UCLA.

The first, and so far only, bispecific antibody on the market, Blincyto (blinatumomab), is approved by the Food and Drug Administration (FDA) to treat some patients with acute lymphoblastic leukemia (ALL). The drug, referred to as a bispecific T-cell engager (also referred to as BiTE), has one arm that attaches to CD3 and a second that binds to the antigen CD19 on the surface of cancerous B cells.

In a trial of patients with relapsed or resistant B-cell precursor ALL, Blincyto increased the rate of complete remissions from 20% among patients on standard-of-care chemotherapy to 42%. In a pediatric study released in March 2021, 69% of children treated with Blincyto were still alive after nearly two years, and 93% showed no sign of disease. In a phase 2 study released in May 2021, there was a 95% response rate among patients with Philadelphia chromosome-positive ALL who received Blincyto plus the targeted drug Iclusig (ponatinib), showing the potential of treating patients without the need for chemotherapy, the researchers said.

Bispecific antibodies can cause side effects, including cytokine release syndrome, a severe inflammatory response marked by high fever, body aches and other symptoms. Although Herman experienced cytokine release after his first shot of teclistamab, he has had minimal side effects since then.

BROADENING THE REACH OF IMMUNOTHERAPY

Bispecific antibodies could bring immunotherapy options to patients who aren’t eligible for treatments like CAR T cells, which are personalized therapies that entail removing immune cells from patients and engineering them to recognize and attack their cancer. Although these T-cell therapies can be lifesaving, they present challenges that could be avoided with bispecific antibodies, says Dr. Joshua Richter, assistant professor of medicine, hematology and medical oncology at the Icahn School of Medicine at Mount Sinai in New York.

“CAR-Ts are not off-the-shelf products, so they take time for manufacturing, whereas bispecifics are off the shelf,” Richter says. And even though there is a risk of side effects with bispecific antibodies, they are titratable, meaning they can be given in small doses to start and then in larger doses after the immune system is given a chance to adapt. “We are concerned about giving CAR-Ts to older people because some can get quite sick (from cytokine release),” Richter says. “It’s nice to have a more titratable alternative.”

Several bispecific antibodies aimed at multiple myeloma are in clinical trials now, some of which are showing early promise. In a phase 1 dose-ranging study of an intravenous formulation of teclistamab, for example, 58% of patients on the recommended dose for phase 2 trials showed a partial response and 30% had a complete response. Although 70% of participants experienced cytokine release, none had symptoms severe enough to prompt them to pull out of the trial. Other side effects included anemia, a drop in white blood cells and fatigue. A phase 2 study of the drug in multiple myeloma is ongoing and recruiting patients.

Another trial of a BCMA-CD3-targeted bispecific antibody, elranatamab, was paused in May because of cases of peripheral neuropathy reported by some patients. The drug’s developer, Pfizer, was asked to investigate the cases and report what it finds to the FDA. Patients in the trial who were benefiting from the drug were able to stay on it, but no new patients will be accepted until the investigation is complete.

There are other promising approaches to multiple myeloma in early-stage testing, Richter says, including a bispecific antibody called cevostamab, which targets CD3 and FcRH5, an antigen expressed on the surface of almost all multiple myeloma cells. Interim results from an ongoing phase 1 study that were reported in December showed an overall response rate of 53%. Responses were even seen in patients who had failed five previous treatments.

Another prospect in multiple myeloma is a bispecific antibody called GBR1342, which targets CD3 and CD38, an antigen implicated in the disease and other blood cancers. The drug, now in phase 1 testing, received orphan drug designation from the FDA in 2019, which could expedite its development path.

There are several bispecific antibodies in development to treat other blood cancers, including acute myeloid leukemia (AML). For example, a drug called flotetuzumab targets CD3 and CD123, a molecule called an interleukin-3 receptor that’s prevalent on malignant cells in AML. In a trial of the drug in patients who had relapsed after other therapies, 32% of participants achieved a response, and more than half of those were able to go on to receive stem cell transplants, which put them in remission.

The flotetuzumab trial results highlighted another potential advantage of bispecific antibodies, which is that they may offer patients a bridge to other treatments that could result in more durable remissions, such as stem cell transplants. The ALL treatment Blincyto has also been shown to offer some patients a good lead-in to stem cell transplants. In a trial comparing the drug to standard-of-care chemotherapy, the overall response rate to Blincyto was 44%, and 24% of the patients receiving the drug went on to have stem cell transplants.

Oncologists at The University of Texas MD Anderson Cancer Center in Houston are now testing Blincyto in patients with newly diagnosed ALL, and there are encouraging early results. Last year, researchers reported results from a small trial in which patients with ALL started with four cycles of chemotherapy and then were placed on maintenance treatments that included Blincyto. There was a 100% response rate, and 79% of patients stayed in remission for two years.

“Historically, we can cure about 40% to 50% of elderly patients with ALL, so if this response rate holds over time, it will be a tremendous improvement, essentially doubling survival rates,” said Dr. Marina Konopleva, a professor and physician-scientist in the department of leukemia and stem cell transplantation at MD Anderson.

Phil Briggs, who received a diagnosis of ALL in January 2018, was treated with Blincyto in the fall of 2020, after his cancer stopped responding to standard-of-care chemotherapy. He found the drug to be far more tolerable than chemotherapy, which had caused him to lose his appetite and drop more than 50 pounds, in addition to developing peripheral nerve damage. Aside from a slight skin irritation, “I felt fantastic,” says Briggs, 62, who is being treated at MD Anderson.

Briggs’ courses of Blincyto came in a portable pump, allowing him to receive the agent on an outpatient basis without having to go to the hospital. After four months on the drug, he was able to undergo a stem cell transplant and is now in remission. “I felt so much better that I was able to go straight from (Blincyto) to the stem cell trans- plant without any side effects,” says Briggs, who is now planning to go back to work as an insurance salesman.

BRINGING BISPECIFICS TO SOLID TUMORS

Targeting solid tumors with immunotherapy has been difficult because they lack a single target for immune cells to latch on to, and the environment that surrounds them may not be conducible for immune cells to readily attack the cancer cells. The two-pronged design of bispecific antibodies could help overcome those hurdles.

Several bispecific antibodies being developed to treat solid tumors include one treatment group that targets an immune checkpoint like PD-L1 or CTLA-4, inhibiting it so the immune system can launch an attack.

For example, a bispecific antibody called FS118, which is now being tested in a phase 1 trial in solid tumors, has one treatment group that inhibits PD-L1 and another that blocks another immune checkpoint called LAG-3. Initial results from a trial released last year showed that patients who had been treated with PD-1 or PD-L1 blockers and became resistant to them had durable stabilization of their disease on FS118.

A bispecific antibody called XmAb20717 blocks PD-1 and CTLA-4 and is being tested in patients with a number of solid tumor types. The response rate in a trial reported last November was 19% and included a complete remission in one patient with melanoma. Partial responses were seen in patients with ovarian cancer, non-small cell lung cancer (NSCLC) and castration-resistant prostate cancer.

Other bispecific antibodies in development to treat solid tumors target disease-promoting genetic mutations. One of these agents was recently approved by the FDA. Called Rybrevant (amivantamab-vmjw), it targets EGFR and MET in NSCLC with abnormalities in those genes. It is the first fully human, bispecific antibody approved in lung cancer. The approval was based on results from the phase 1 study, where the response rate to the drug was 40% in patients who had previously been treated with platinum chemotherapy, and 74% of patients saw their disease stabilize.

With so many bispecific antibodies in development across a range of cancer types, many patients could benefit from enrolling in clinical trials of these new therapies, says Wong. “Clinical trials are a good option to consider, especially if you’ve already been on standard therapies,” she says. “It may be that patients who responded well to their initial therapy and then developed resistance could be good candidates for bispecific antibodies.”

And because bispecifics target the immune system, they could improve the prognosis for many patients, Wong says: “The beauty of immunotherapy is that the immune system has a long memory, so there’s a potential for patients to have long-lasting responses to these drugs.”

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