Bispecific Antibodies Could Be the Next Big Advance in Oncology

Human monoclonal antibody therapies are among the fastest growing categories in the cancer pipeline, with more than 570 agents in clinical development.¹ Now, a new
type of antibody-based therapy may overcome the limitations of monoclonal antibodies, and it has the potential to disrupt the current treatment paradigm in oncology.

Bispecific antibodies are proteins engineered to recognize 2 different targets at the same time. Therapeutics based on bispecific antibodies are becoming increasingly important in cancer treatment, especially in hematology, said Carol O’Hear, MD, PhD, global development leader at Genentech, a member of the Roche group.

“Because of their distinct mechanism of action, which is different from cytotoxic chemotherapy or targeted agents, they have an ability to expand upon the current treatment options that are available by harnessing the potential of a person’s immune system to fight their cancer,” she added.

So far, 2 such therapeutics are available in the United States. Amgen’s blinatumomab (Blincyto) was given accelerated approval for the treatment of B-cell precursor acute lymphoblastic leukemia, and Roche/Chugai’s emicizumab (Hemlibra) was approved by the FDA in October 2018 to treat patients with hemophilia.

There are more than 300 bispecific antibodies in development. The global market for these therapeutics is predicted to reach $10 billion by 2026, according to a report last year by Kuick Research.2 The most common bispecific antibodies in development target a tumor-associated antigen on a cancer cell and CD3 on T cells. These treatments make up about 45% of the bispecific pipeline.

Genentech is at the forefront of bispecific antibody development. The company presented new data at the 2020 American Society of Hematology (ASH) annual meeting in December for several of its developmental agents. Two of these—mosunetuzumab and glofitamab—are T-cell-engaging bispecific antibodies that target CD20 and CD3 and are designed to bind to the cancer cell and the T cell simultaneously.

This enables the immune system to redirect a patient’s existing T cells to engage and eliminate targeted cancer cells by releasing cytotoxic proteins into the cancer cell. Both agents show promising, durable results in patients with elapsed or refractory (R/R) non-Hodgkin lymphoma (NHL). “These patients are typically known to have poor prognoses with standard therapy,” O’Hear said.

She pointed out that in follicular lymphoma (FL) specifically, disease progression within 2 years of initial therapy is a poor prognostic factor.

At the 2020 ASH meeting, data presented for the GO29781 trial (NCT02500407) was focused on mosunetuzumab activity in FL and showed an overall response rate (ORR) of 67.7% and a complete response rate (CR) of 51.6%. GO29781 is a phase 1/1b, multicenter, open-label, doseescalation study evaluating the safety and pharmacokinetics of mosunetuzumab in people with B-cell NHL.³ The findings showed consistent response rates across typically poor prognostic subgroups.

At ASH’s annual meeting in 2019, investigators presented data that demonstrated a CR rate of 43.3% (n = 67) in slow-growing NHL and 19.4% (n = 124) in aggressive NHL.⁴ For glofitamab, new data from the phase 1/1b NP30179 study (NCT03075696) showed that, as a monotherapy, it achieved an ORR of 60.7% and a CR 53.6% in aggressive NHL.⁵

At the ASH meeting in 2019, data presented showed that in combination with Genentech’s obinutuzumab (Gazyva), the CR rate in patients with R/R NHL was 46% (n = 28).

One of the most common adverse events for both bispecific antibodies is cytokine release syndrome (CRS). In these trials, CRS was mainly grade 1/2, occurred in early treatment cycles, and was mostly reversible.

O’Hear said mosunetuzumab specifically has potential in earlier treatment settings, providing an option for patients unable to tolerate immunochemotherapy. She highlighted early from the phase 1/2 GO40554 study (NCT03677154) to treat patients with diffuse large B-cell lymphoma in the frontline setting. Initial data show a CR rate of 42%

References

1. Lu RM, Hwang YC, Liu IJ, et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci. 2020;27(1):1. doi:10.1186/ s12929-019-0592-z
2. Global bispecific antibodies therapy Blincyto Hemlibra therapeutics market size to witness 118% growth to reach US$10 billion by 2026. News release. Kuick Research. October 7, 2020. Accessed January 28, 2021. prn.to/3cgC3Bm
3. Assouline SE, Kim WS, Sehn LH, et al Mosunetuzumab shows promising efficacy in patient with multiply relapsed follicular lymphoma: updated clinical experience from a phase 1 dose-escalation trial. Presented at: 2020 American Society of Hematology. December 5-8, 2020. Abstract 702. bit.ly/2MJLFKw
4. Genentech announces new data on novel CD20-CD3 bispecific cancer immunotherapies in people with difficult-to-treat lymphomas. News release. Genentech. December 7, 2019. Accessed January 28, 2021. bit.ly/39rZXI9
5. Roche presents new data from its bispecific antibody portfolio across a range of blood cancer. News release. December 8, 2020. Accessed January 28, 2021. bit.ly/3aER916