CD20/CD3 Bispecific Antibodies Can Revolutionize B-Cell Lymphoma Therapy

Loretta J. Nastoupil, MD

Over the last several decades, the management of B-cell lymphoma has been transformed by advancements in the therapeutic landscape, not the least of which is the evolution of bispecific antibodies (bsAbs).¹ Unlike conventional monoclonal antibodies (mAbs), which are monospecific, bsAbs bind 2 epitopes simultaneously, either on the same antigen or 2 distinct antigens.² These molecules exist in many formats and are customizable based on indication (FIGURE 1¹ ).

The bispecific antibodies...under development for B-cell lymphoma target CD20, and they have a second receptor that targets CD3, which is present on vector T cells,” said Loretta J. Nastoupil, MD, an associate professor in the Department of Lymphoma/ Myeloma at the University of Texas MD Anderson Cancer Center in Houston during an interview with Targeted Therapies in Oncology™. She added that the dual antigen nature of bsAbs allows direct immune system and tumor engagement by inducing T-cells in response to malignant B-cells, resulting in tumor cell lysis.¹

“We think [bsAbs] is going to be a potentially even more effective strategy than just the naked monoclonal antibody,” Nastoupil said.

The Relapsed/Refractory Setting

Like chimeric antigen receptor (CAR) T-cell therapy, bsAbs have shown durable response in patients with relapsed/refractory (R/R) B-cell lymphomas, such as diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).³

“With the single agent in patients who are heavily pretreated, we’re seeing remarkable response rates that are close to 50% to 60%,” Nastoupil said. “It is rare for [these] patients [to] actually have a complete response, and the remission duration was quite short, with many patients expecting a median overall survival of about 6 months prior to these newer therapies coming into the treatment landscape.”

“Thinking about it in terms of what was available historically for these patients, this is a substantial improvement,” added Nastoupil.

Bispecific Antibodies as Upfront Therapy

Trials exploring the use of bsAbs beyond the relapsed/refractory setting, such as the combination of chemotherapy or other immunotherapeutic agents in the upfront DLBCL setting, are ongoing. If these studies are successful, such combination therapy may preclude the need for initial intensive chemotherapy, especially in the frail and elderly.³

“As they [bsAbs] move into earlier lines of therapy, they’re being combined,” said Nastoupil. However, the question of effectiveness remains. “It’ll be some time before we see the randomized studies emerge that will let us know conclusively whether or not it’s better than what we currently have available,” she added. “But there is a lot of promise and enthusiasm surrounding these agents, particularly as we use them in patients that are less heavily pretreated.”

Historical Development of Bispecific Antibodies

The technological origins of bsAbs can be traced back to the 1960s when Nisonoff and coworkers first proposed mixing different antibody fragments to produce multispecifi c antibodies.⁴ Köhler and Milstein subsequently developed the hybridoma technique to create bispecifi c antibodies.^5,6 However, low yields of the targeted pair and unanticipated immunological responses plagued this method.⁷

In 1984, Staerz et al discovered the first bsAb capable of attracting T cells to decrease the growth of tumors in vivo.⁷ Then, in 2009, catumaxomab became the fi rst bsAb authorized for therapeutic use. However, it was withdrawn shortly afterward because of deadly hepatotoxicity associated with intravenous administration.⁸ Later blinatumomab (Blincyto), a CD3/CD19 bsAbs, demonstrated clinical success in treating R/R acute lymphoblastic leukemia.⁹ Its subsequent approval has helped accelerate bsAb development and clinical adaptation in treating lymphomas.³

Emerging Therapy

Several CD20/CD3 bsAbs are showing promising clinical activity against B-cell lymphoma. In heavily pretreated patients with R/R B-cell non-Hodgkin lymphoma (B-NHL), glofi tamab treatment achieved a clinically signifi cant complete response (CR) rate at doses of 10 mg or greater in 49.3% of patients. Moreover, in those with high tumor burden, bulky disease, and refractoriness to multiple treatments, CRs were achieved rapidly.¹⁰

A phase 2 study (NCT02500407) involving patients with R/R follicular lymphoma showed that fi xed-duration mosunetuzumab demonstrated a high objective and complete response rate in a heavily pretreated patient population. A reduction in tumor size was seen in 95% of evaluable patients, the safety profi le was manageable, and most patients had a CR (FIGURE 2¹¹), according to investigators. “We’re anticipating [mosunetuzumab] will be approved for R/R follicular lymphoma this calendar year in the US,” said Nastoupil.

In a phase 1/2 study, 18 patients with DLBCL who received a 12mg or greater dose of epcoritamab achieved an overall response rate (ORR) and CR of 66.7% and 33.3%, respectively. Seven patients who received 48mg or greater achieved an ORR of 100%.¹² By next calendar year, approval of epcoritamab for R/R DLBCL is likely, noted Nastoupil. In patients with R/R follicular lymphoma, odronextamab achieved an ORR and CR of 92.9% and 75%, respectively. Moreover, twenty-one patients with DLBCL, refractory to CAR T-cell therapy, treated at doses of 80mg or greater, achieved an ORR and CR rate of 33.3% and 23.8%, respectively.¹³

Another therapeutic, IGM-2323, an IgMbased CD20/CD3 bsAb, is being tested in people with R/R B-NHL.¹⁴ Results from a phase I study showed excellent safety and tolerability profile up to 1000 mg and rapid and deepening response patterns.¹⁵

Toxicity and Management of Adverse Events

Activation of the immune system can lead to severe and specific complications such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Fortunately, CRS associated with bsAb therapy is primarily low-grade. Management generally consists of intravenous fluids, antipyretics, and antihistamines.³

Regardless, higher-grade CRS can become an issue. “The problem is those rare situations where [patients] progress from grade 1 to grade 2 or higher,” said Nastoupil. “Those are the patients that are going to be hospitalized, and they may need supportive care and sometimes even aggressive supportive care.” Currently, the treatment for higher-grade CRS is monitoring organ function in the intensive care unit, tocilizumab (Actemra), and corticosteroids.¹⁶

Mitigation strategies, like premedication with steroids, antihistamines, and acetaminophen, are employed with bsAb therapy to reduce CRS occurrence.³ One approach is step-up dosing. “Most patients will start outpatient,” said Nastoupil. “They undergo…a dose ramp up or step up where they get a low dose on day one, a slightly higher dose on day eight, and then they get the full dose by day 15. So, you’re not overwhelming these T cells all at once.”

Immune effector cell-associated neurotoxicity syndrome is a pathological process of the central nervous system involving the activation of endogenous or infused T-cells.¹⁷ The most common symptoms of ICANS include headache, tremor, expressive dysphasia, apraxia, and lethargy. Global aphasia, akinesia, and seizures appear late. Management of ICANS involves excluding other causes of neurotoxicity, head elevation, aspiration precautions, high-dose corticosteroids, and mechanical ventilation, if necessary.³

Bispecific Antibody Versus CAR T-cell Therapy

Although CAR T-cell therapy has become a mainstay of R/R aggressive B-cell lymphoma management, it has certain limitations. First, infusions may be delayed. Second, patient identifi cation to manufacturing is unreliable. Lastly, the final product may not always generate a response.¹⁸

On the other hand, bsAbs are an offthe-shelf option that do not require T-cell preparation ex vivo.¹⁸ “You don’t have that lag time from the time CAR T is considered until [patients] actually get seen at a center,” remarked Nastoupil. “You don’t have to wait for a manufacturing slot, and then you don’t have to wait for the manufacturing time.” She added that more readily available therapy is beneficial when time is a factor.

Both therapies have a comparable toxicity profi le, and while bsAb adverse effects appear less severe and less frequent, toxicological data are still in their infancy. Additional toxicities of interest seen with bsAb therapy include pyrexia, injection site reactions, headaches, and cytopenia (FIGURE 3¹⁸). Regardless, methods like step-up dosing, alternative administration routes, or cytoreductive mAbs may allow for higher-dose drug administration and increased response rates of bsAb therapy compared with CAR T-cell therapy.¹⁸

With CAR T-cell therapy, however, longterm data suggest that responses are durable, particularly for patients with complete responses. Response rates to bsAb treatment can vary widely and may be infl uenced by previous CAR T exposure. However, given the limited experience with bsAbs, longterm follow-up and evidence on response durability are poor.¹⁸

Clinical Trials of Interest

Several pivotal bsAb trials are underway. One such trial is MagnetisMM-3 (NCT04649359), a phase 2 study evaluating the safety and effi cacy of elranatamab monotherapy in patients with R/R multiple myeloma. Preliminary results indicate that a 2-step-up priming regimen of elranatamab is well-tolerated in patients without prior B-cell maturation antigen (BCMA) therapy. Moreover, no cases of grade ≥3 CRS or ICANS were observed.¹⁹

The Phase 2 NP30179 expansion study (NCT03075696) showed that glofi tamab with obinutuzumab pretreatment induced durable CR in patients with R/R DLBCL and ≥2 prior therapies, including previous CAR T-cell exposure. Additionally, due to effective step-up dosing, CRS were mainly graded I or II.²⁰ Results from phase 1/2 MajesTEC-1 trial (NCT04557098) demonstrated that monotherapy with teclistamab induced durable responses and manageable safety profi le in heavily pretreated patients with R/R MM.

Lastly, AK104 combined with standard therapy has shown encouraging antitumor activity in patients with recurrent or metastatic cervical cancer (R/M CC; NCT04868708). Grade ≥3 adverse events occurred in 51.1% of patients. However, longterm safety evaluation is ongoing.²²

Looking Toward the Future

Bispecific antibodies offer a viable over-thecounter therapeutic option for R/R B-cell lymphoma that may outperform prior therapy. However, the long-term effectiveness and tolerability of bsAbs, optimal therapeutic combinations, and appropriate timing of therapy remain uncertain.¹ “As these bispecifics enter into the treatment landscape, they’ll most likely be approved fi rst in the third line or later space,” said Nastoupil. However, with further studies and longer-term follow-up data, this may change.

“Do we use [bsAb] post-CAR T? Do we use [bsAb] instead of CAR T in large cell lymphoma for certain patients? When would be the preferred time to use [bsAbs]? Does it matter if [patients] had chemotherapy recently? These are all the questions that we’ll probably have to answer with real-world data,” concluded Nastoupil.

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