Bispecific Antibodies: Successes and Challenges

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Bispecific T-cell engager (BiTE) antibodies, such blinatumomab, may be the most appealing type of bispecific antibodies, a class of manufactured constructs that is expected to expand into the solid tumor space, according to Hermann Einsele, MD, Professor of Medicine at the University of Würzburg, Germany. Dr. Einsele updated listeners on blinatumomab and other bispecific antibodies at the 2020 ASCO-SITC Clinical Immuno-Oncology Symposium.1

Hermann Einsele, MD

Hermann Einsele, MD

Bispecific antibodies tackle two main problems seen with chimeric antigen receptor (CAR) T-cell therapy: the potential that antitumor reactive T cells will be insufficient in number or dysfunctional and anergic. The question now is whether they will be more effective and less toxic. “Are they perhaps the ‘poor man’s’ CAR T cells? The race is ongoing,” he said.

The bispecific antibodies developed so far are either fragment-based, symmetric, asymmetric, or BiTEs. These formats determine their half-life, level of immunogenicity, target specificity, and manufacturing difficulty. Among them, BiTE antibodies have the most favorable characteristics, according to Dr. Einsele.

“The aim with BiTE antibodies is to increase the frequency of tumor-reactive T cells,” he explained. To this end, BiTE antibodies create an immunologic synapse between the tumor cell and the T cell. Their activation is achieved independently of major histocompatibility complex class 1/2, co-stimulation, or peptide antigen presentation. Classical BiTE antibodies (blinatumomab, AMG-420, and others in development) are also effective at low concentrations.

“The aim with bispecific T-cell engager antibodies is to increase the frequency of tumor-reactive T cells.”
— Hermann Einsele, MD

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The one bispecific antibody that has been approved for use in the clinic is a BiTE antibody. Blinatumomab targets CD19 and CD3 and is indicated for the treatment of B-cell acute lymphoblastic leukemia (ALL).

Dealing With Neurotoxicity

Because of their short half-life, BiTE antibodies must be given as a continuous infusion. Although this is inconvenient, it also has a positive side: treatment can be stopped immediately when toxicity (cytokine-release syndrome, neurotoxicity) arises.

Neurotoxicity is, in fact, commonly observed with blinatumomab. As explained by Dr. Einsele: “Blinatumomab increases the adhesiveness of T cells to the vascular endothelium. This allows the T cells to extravasate and move into the central nervous system (CNS), where they target B cells, produce local cytokines, and induce transmigration of monocytes, which further increase local inflammation and thus neurotoxicity.”

Management of neurotoxicity includes step dosing and preemptive use of corticosteroids. “We do a handwriting analysis, looking for signs of neurotoxicity. If necessary, we intervene with dexamethasone as soon as possible. With this strategy, most patients can actually obtain the full dose of blinatumomab,” said Dr. Einsele.

“Patients with MRD-positive disease achieving MRD negativity with blinatumomab enjoyed long-term, progression-free survival without an additional transplant.”
— Hermann Einsele, MD

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He has also begun applying an antiadhesive agent to disrupt blinatumomab-induced interactions between T cells and vascular endothelial cells, using the P-lectin antagonist pentosan polysulfate. “We have shown that this reduces the adhesion of T cells to the endothelium, thereby decreasing local cytokine release and CNS toxicity,” he noted.

Bispecific antibodies targeting CD19 and CD20 can also cause depletion of B cells and plasma cells, which can last a year or longer, putting patients at increased risk for bacterial infection. Opportunistic infections are also seen with bispecific antibodies, possibly due to chronic and massive antigen stimulation and T-cell exhaustion.

Update on Efficacy of Blinatumomab

Blinatumomab was evaluated in 70 patients treated with a median of three prior lines of therapy for non-Hodgkin lymphoma.2 Responses were observed in 90% of patients with follicular lymphoma, 71% with mantle cell lymphoma, and 55% with diffuse large B-cell lymphoma, with complete responses achieved by about 40% of each cohort. After about 10 years of follow-up, approximately 40% of patients who achieved complete or very good partial remissions had ongoing responses, and almost 60% remained alive.3

In B-cell ALL, efficacy seems to correlate with the number of previous therapies and tumor load. Complete response rates were 29% for heavily pretreated patients with a high tumor load, 69% for early-relapse patients lacking a high tumor load, and 80% for patients treated for minimal residual disease (MRD) after intensive chemotherapy.4

In contrast to studies of CAR T-cell therapy, blinatumomab was compared with standard-of-care chemotherapy, showing a significant advantage in overall survival (hazard ratio = 0.71; P = .012). After 30 months, 28% of patients were still alive, and most had undergone an allogeneic stem cell transplantation, suggesting that in relapsed or refractory ALL, “the bispecific antibody is kind of a bridge to transplant,” he commented. In contrast, patients with MRD-positive disease achieving MRD negativity with blinatumomab “enjoyed long-term, progression-free survival without an additional transplant.”

Retreatment With Blinatumomab

“The question now is whether blinatumomab consolidation can replace allogeneic stem cell transplantation for higher-risk patients with ALL,” posed Dr. Einsele. “Another question is whether we can retreat patients.”

“Bispecific antibodies will move into earlier lines of treatment, especially after induction and consolidation with transplant, in patients at high or ultra-high risk of disease progression.”
— Hermann Einsele, MD

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Retreatment proved effective, in fact, in a study of patients who relapsed after blinatumomab and transplantation, of whom 36% responded to retreatment with blinatumomab—almost as many as responded to initial treatment (44%).5 Three out of four responding patients were still alive up to 20 months later, “despite the fact that they had received blinatumomab treatment before, plus an allogeneic stem cell transplant,”
he noted.

Other bispecific antibodies may also be effective in the retreatment setting, according to a study of mosunetuzumab, a CD20/CD3-targeting bispecific antibody. The complete response rate of 22% was achieved by patients whose disease failed to respond to CAR T-cell therapy.6

The BiTE Program in Würzburg

“We’ve been fortunate to be involved in the whole development program of blinatumomab. Because we were really excited about this bispecific antibody, we have established quite a large program to study BiTE antibodies in solid tumors,” Dr. Einsele continued. The solid tumor program is evaluating investigational BiTEs in colorectal, stomach, lung, and prostate cancers as well as in glioblastoma.

“In patients with prostate cancer, we have now seen four good responses, including one patient in complete remission after treatment with bispecific antibodies targeting B-cell maturation antigen (BCMA). We also have two patients with relapsed glioblastoma who responded to a bispecific antibody,” he reported.

The main development, however, is still in hematologic malignancies. To this end, multiple myeloma is a major target for bispecific antibodies. In a proof-of-concept study, the BCMA-targeting bispecific antibody AMG-420 produced responses in 70% of heavily pretreated patients, including MRD and ongoing remissions in several.7 Because of the need for continuous infusion, however, Amgen has discontinued development of AMG-420 in favor of pursuing the next-generation AMG-701, which has an extended half-life that allows weekly dosing.

CC-93269 Bispecific Antibody

Promising results are being reported for the next-generation BCMA-binding bispecific antibody CC-93269. The antibody is given weekly for 3 months, then every 2 weeks for 6 months, and then monthly for up to 2 years. In heavily pretreated patients with multiple myeloma, a response rate of 88% was observed, with 44% being complete responses; most of the high-dose cohort has remained in remission.8 Cytokine-release syndrome was severe in just one patient, although infectious complications and cytopenias were common.

Dr. Einsele predicted that bispecific antibodies will move into earlier lines of treatment, especially after induction and consolidation with transplant, in patients at high or ultra-high risk of disease progression. “Patients with early relapse after transplantation might also be good candidates,” he added. “Because of their low toxicity, non–transplant-eligible patients who are receiving induction therapy might also be.”

Lessons Learned and Problematic Issues

What has been learned from clinical trials is that bispecific antibody constructs can, as single agents, induce clinical responses in patients with B-cell ALL, non-Hodgkin lymphoma, and multiple myeloma, resulting in a cure for some patients, Dr. Einsele summed up. However, resistant mechanisms remain problematic, including immune escape, insufficient drug or cell penetration, and a hostile tumor microenvironment. These issues might be addressed using local irradiation, the addition of checkpoint inhibitors, and combinations of bispecific antibodies with different antigen targets, he suggested.

DISCLOSURE: Dr. Einsele has served as a consultant or advisor to or received honoraria or travel findings from Celgene, Janssen, Amgen, Bristol-Myers Squibb, Takeda, and Novartis.


1. Einsele H: Bispecific antibodies for hematologic malignancies: Successes and challenges. Invited lecture at the 2020 ASCO-SITC Clinical Immuno-Oncology Symposium. Presented February 7, 2020.

2. Goebeler ME, Knop S, Viardot A, et al: Bispecific T-cell engager antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma: Final results from a phase I study. J Clin Oncol 34:1104-1111, 2016.

3. Dufner V, Sayehli CM, Chatterjee M, et al: Long-term outcome of patients with relapsed/refractory B-cell non-Hodgkin lymphoma treated with blinatumomab. Blood Adv 3:2491-2498, 2019.

4. Kantarjian H, Stein A, Gökbuget N, et al: Blinatumomab vs chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 376:836-847, 2017.

5. Topp MS, Stelljes M, Zugmaier G, et al: Blinatumomab retreatment after relapse in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia. Leukemia 32:562-565, 2018.

6. Schuster SJ, Bartlett NL, Assouline S, et al: Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-cell therapies, and is active in treatment through multiple lines. 2019 ASH Annual Meeting & Exposition. Abstract 6. Presented December 8, 2019.

7. Topp MS, Duell J, Zugmaier G, et al: Anti-B-cell maturation antigen BiTE molecule AMG 420 induces responses in multiple myeloma. J Clin Oncol 38:775-783, 2020.

8. Costa LJ, Wong SW, Bermúdez A, et al: First clinical study of the B-cell maturation antigen 2+1 T cell engager CC-93269 in patients with relapsed/refractory multiple myeloma: Interim results of a phase I multicenter trial. 2019 ASH Annual Meeting & Exposition. Abstract 143. Presented December 7, 2019.