Development and Clinical Application of CD19xCD3 and CD20xCD3 Bispecific Antibodies

One of the unique approaches in cancer immunotherapy is the use of bispecific antibodies. Andreas K. Klein, MD, provides an overview of the development of CD19xCD3 and CD20xCD3 bispecific antibodies and their clinical application in the treatment of hematologic malignancies. Dr Klein is acting chief of the Division of Hematology/Oncology, director of the Hematologic Malignancies Program, and director of the Bone Marrow and Hematopoietic Cell Transplant Program at Tufts Medical Center, and an associate professor of medicine at Tufts University School of Medicine in Boston, Massachusetts.

Could you provide a brief overview of the clinical development of bispecific antibodies?

The development of bispecific antibodies goes back a decade. These are constructs that aim to redirect T cells against the tumor. T cells have some natural reactivity against tumor cells, and there may be rare circulating T cells that are able to recognize leukemia or solid tumors, but there are not enough of them. Those cells are easily exhausted and they are not up to the task of fighting off and eliminating the leukemia and lymphoma once they develop.

The idea was to recruit more of those T cells to join the fight and one way is with tumor vaccination. This worked in vitro but not in practice. Experiments with tumor vaccination led to the discovery that there are 2 arms to the T-cell immune system: the effector arm that does the killing and the regulatory arm that modulates the immune reactions and prevents them from getting out of control. When we analyzed tumor vaccines in the lab, there were great T-cell responses. However, in patients, the effector actions were balanced by regulatory reactions and in the end, the strategy just did not work. 

The question then was whether we could use an antibody construct to force the tumor and T cell together, where an antibody would stick to a tumor cell and grab an innocent T cell that is floating around, hold it up against the target cell, cause activation of the T cell, and kill the target.²

Among the many challenges we faced in making that work, one of the first was how to create a construct that can activate the immune system without eliciting a response in the same immune system that would result in clearance of the therapeutic agent. For example, the CD19xCD3 bispecific antibody blinatumomab, which is among the first bispecific antibodies to reach the market, has to be given by continuous infusion because it is cleared so quickly due to the antibody’s small size. Continuous infusion is technically burdensome because it requires a lot of resources, preparation, planning, and management of the patient with an at-home pump. Regarding the other bispecific antibodies in development, much of the work is focused on making the delivery schedule more patient-friendly compared with continuous infusion, whether that translates to a daily vs weekly schedule or subcutaneous vs intravenous delivery.

The US Food and Drug Administration (FDA) first approved blinatumomab for the treatment of Philadelphia chromosome-negative (Ph-) R/R B-cell precursor ALL in 2014. In 2017, this approval was expanded to include patients with Ph+ B-cell precursor ALL.³ What is the goal of treatment with blinatumomab?

Blinatumomab is typically used as a bridge to allogeneic stem cell transplant in patients with ALL that is refractory to chemotherapy. The competing treatment is CAR T-cell therapy, which involves a single infusion of a product whose effects may endure throughout the patient’s lifetime, whereas the bispecific antibodies are only active for the duration of their administration. It does not appear that patients are cured with either strategy alone. For most patients with relapsed ALL, allogeneic transplant is the only curative option.

Bispecific antibodies have the advantage of being immediately available, whereas CAR T cells are manufactured over a period of several weeks. In these patients, time is often critical, and the window of opportunity to control the disease is limited. Bridging therapy can provide the necessary time to get everything in place to proceed with the transplant. Blinatumomab has recently gained approval for consolidation of detectable residual disease after initial treatment, and several abstracts presented at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition reported on further extension to combinations with chemotherapy in both low- and high-risk ALL populations.

What types of toxicities are associated with bispecific antibody therapy?

Similar to CAR T-cell therapy, patients undergoing treatment with bispecific antibodies can have a constellation of profound reactions called cytokine release syndrome (CRS) and neurologic toxicities.¹ CRS is caused by release of cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF), in response to immune activation against the tumor. The neurologic toxicity is not as well understood. It is possible that the cytokines produced by the action of the T cells cross into the brain, or perhaps certain immune cells in the brain are triggered to release those same signals within the brain, leading to neurotoxicity. ICANS can have a range of effects from a simple headache to confusion, unconsciousness, and seizures. Both CRS and ICANS are common in bispecific antibody treatments and CAR T-cell therapy.

How are these toxicities managed?

The insight into addressing toxicities associated with bispecific antibody therapy came from the CAR T-cell world. The cornerstone of management is use of an anticytokine agent like tocilizumab (anti-IL-6), anakinra (anti-IL-1),¹ or infliximab (anti-TNF-α), essentially in that order. Steroids are probably safe to use as well, but anticytokine therapy is preferable for the management of CRS. Anticytokine therapy does not seem to do much to reduce or protect against neurotoxicity, so that is managed with steroids and supportive care.

What CD20xCD3 antibodies are now in development for the treatment of non-Hodgkin lymphoma (or other hematologic malignancies)?

Studies of at least 7 bispecific antibodies directing T cells against mature B cells (and these are called bispecific T-cell engagers, or BiTE^®) were presented at the annual ASH meeting in December 2021. While none of these agents has been approved by the FDA, their activity appears to be similar with all yielding high overall complete response rates (ORRs). Glofitamab and mosunetuzumab, which differ only in the number of CD20 binding regions, demonstrated meaningful clinical activity both as single agents for indolent lymphoma (ORRs, 81% and 78.9%, respectively)^4,5 and in combination with polatuzumab vedotin (ORRs, 73% and 65%, respectively),^6,7 an antibody-drug conjugate targeting CD79b, in patients with aggressive lymphomas. Both glofitamab and mosunetuzumab appeared to be associated with manageable side effects. Similarly, subcutaneous epcoritamab^8,9 and intravenous plamotamab¹⁰ showed encouraging activity in both R/R indolent and aggressive settings.

What is the outlook for bispecific antibodies? Where do you see the most potential for their clinical application?

The primary competitor in this space is CAR T-cell therapy, which carries known significant challenges in terms of time to manufacture: you have to identify the patient, collect their cells, send them for manufacture, and infuse them back into the patient. Currently, there is no approved, off-the-shelf CAR T-cell therapy. I do expect that at some point in the future, we will see both the approval of CD20-targeting bispecific antibody therapies and off-the-shelf CD20-targeting CAR T-cell therapies, and it will be exciting to see how the 2 technologies will play out. 

At the same time, enhancements to bispecific antibodies may be on the horizon. For instance, there were studies presented at ASH regarding IGM-2323, a high-avidity bispecific IgM monoclonal antibody with 10 CD20 binding domains¹¹; ADG152, which conditionally engages activated T cells and constrains activity to the region of the tumor¹²; and Aleta-001, which is specifically developed to restore CAR T-cell activity in the setting of antigen loss.¹³ A group from Ludwig Maximilians-Universitӓt München in Germany presented an in vitro analysis of intermittent treatment in a CD19xCD3 bispecific model that led to reinvigoration of T-cell responses, suggesting that pulsing exposure may prove more efficacious than continuous dosing by avoiding T-cell exhaustion.¹⁴

Given the way we develop therapies in the United States, we probably will not see a head-to-head comparison between bispecific antibody and CAR T-cell therapies any time soon. I think there will be space in the market for both bispecific antibody and CAR T-cell therapies. Bispecific antibody therapy may be a better option for patients who are less fit, as therapy may be immediately available and easier to obtain, and doses are easier to titrate compared with CAR T-cell therapy. In addition, there may be opportunities to combine bispecific agents with chemotherapies, immunotherapies, or chemoimmunoconjugates.