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Three years ago, when I wrote analyses on the CD3 bispecific antibody combined ADC, it was often considered an overly aggressive therapy. However, Roche has made significant explorations in this area. When the CD3/DLL3 ADC from Wuxi Biologics was released, many in the industry were puzzled, but there is no need for surprise. Wuxi Biologics’ CD3 bispecific platform is very clever; they designed it as a CD3/DLL3 ADC, and there are not many issues conceptually.
Taking LBL-034 as an example, it can be seen that its binding to T cells is very weak.
Wuxi Biologics cleverly utilizes spatial steric hindrance.
CD3 activation activity will only be exerted when TAA antibodies are bound.
The early research team at Wuxi Biologics is composed of very capable and innovative young individuals. Therefore, their ideas are worth referencing. I believe that once Wuxi Biologics’ CD3/DLL3 ADC enters clinical trials, the results will astonish the industry. The concept is quite simple; Wuxi Biologics’ CD3/DLL3 ADC integrates the characteristics of CD3 bispecific antibodies and ADCs, based on Wuxi Biologics’ unique CD3 bispecific platform. Once this molecule is refined and the activities of CD3 and the toxin are coordinated, it will certainly find its application. In fact, as terminally differentiated cells, the design of Wuxi Biologics for these T cells has very limited killing capability, which may not even be detectable in vitro.
Combining PD1 antibodies with chemotherapy has already become a clinical practice, so there is no need to overly worry that immunotherapy combined with chemotherapy will weaken efficacy. CD3 bispecific antibodies are gradually joining the ranks of IO combined ADCs.
The R&D capabilities of Chinese biotech are rapidly advancing to the forefront of the world. The creativity from scratch is now being driven by the post-80s and post-90s generations in China.For instance, the IBI363 from Innovent was once not well-regarded, both internally and externally, but its current efficacy has astonished the industry. The person in charge is also a post-85 individual, who has now entered the senior management ranks at Innovent.
As a professional in the primary market investment industry, there is no reason not to invest in the emerging post-80s generation in China. They are the true backbone of China’s innovative drug development.
On May 12, 2019, Genentech announced patents related to the combination of Mosunetuzumab (CD20XCD3 bispecific antibody) with Polatuzumab vedotin (targeting CD79b IgG1 MMAE) ADC, focusing on the administration scheme.
This clinical trial started in 2018 and has taken years to deeply explore the clinical dosing administration scheme.
Recently, the results have finally come to fruition. On June 20, 2025, Roche announced that the combination of Lunsumio and Polivy significantly extends the remission period for patients with relapsed or refractory large B-cell lymphoma.
Roche announced the results of the Phase III SUNMO [NCT05171647] study, which showed that for patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) who are not suitable for transplantation, the subcutaneous injection of Lunsumio (mosunetuzumab) combined with Polivy (polatuzumab vedotin) significantly improved the primary endpoints of progression-free survival (PFS) and objective response rate (ORR) compared to MabThera/Rituxan (rituximab), gemcitabine, and oxaliplatin (R-GemOx).The SUNMO study results will be submitted to global health authorities, including the U.S. Food and Drug Administration (FDA). The National Comprehensive Cancer Network (NCCN) recently included Lunsumio and Polivy in the NCCN Clinical Practice Guidelines for Oncology (NCCN Guidelines) as a 2A recommended treatment for second-line (2L) diffuse large B-cell lymphoma (DLBCL) patients who are not planning to undergo transplantation.Dr. Levi Garraway, Roche’s Chief Medical Officer and Global Product Development Head, stated: “Lunsumio and Polivy represent the first combination of bispecific antibodies and antibody-drug conjugates, which can avoid chemotherapy and may provide another treatment option for some relapsed or refractory LBCL patients. The good safety profile and outpatient potential of this regimen are also encouraging, as it may meet the needs of different patients and healthcare systems.”In a median follow-up of 23.2 months, the combination of Lunsumio and Polivy reduced the risk of disease progression or death by 59% compared to R-GemOx (hazard ratio [HR] 0.41, 95% confidence interval [CI]: 0.28–0.61; p<0.0001). The median PFS for the Lunsumio and Polivy group was 11.5 months (95% CI: 5.6-17.6), three times that of the R-GemOx group at 3.8 months (95% CI: 2.9-4.1), with a 12-month PFS more than double that of the R-GemOx group, at 48.5% (95% CI: 39.6-57.4) versus 17.8% (95% CI: 5.4-30.3). This PFS benefit was consistent across all subgroups, including high-risk patients with primary refractory disease (HR 0.46, 95% CI: 0.29-0.72). Overall survival (OS) data for the interim analysis were not mature. The OS for the Lunsumio and Polivy combination was numerically superior, with a median survival of 18.7 months (95% CI: 14.1 – not evaluable [NE]), compared to 13.6 months (95% CI: 9.9 – NE; HR 0.80; 95% CI: 0.54 – 1.20) for the R-GemOx regimen.Jason Westin, a professor of lymphoma at the University of Texas MD Anderson Cancer Center and director of lymphoma clinical research, stated: “For patients with this refractory disease, we still urgently need effective and well-tolerated treatment options. If approved, this ready-to-use treatment combination of mosunetuzumab and polatuzumab vedotin can be administered within a fixed timeframe without the need for mandatory hospitalization or traditional chemotherapy, providing a meaningful treatment option for relapsed or refractory LBCL patients.”The proportion of patients achieving objective response in the Lunsumio and Polivy combination group (70.3%, 95% CI: 61.9-77.8) was 30% higher than that in the R-GemOx group (40.0%; 95% CI: 28.5-52.4), with a complete response rate (CR) of 51.4% (95% CI: 42.8-60.0) versus 24.3% (95% CI: 14.8-36.0), effectively doubling. Nearly 75% of patients with complete response remained in remission one year later (72.6%; 95% CI: 61.4-83.8), compared to 44.1% (95% CI: 13.2-74.9) in the R-GemOx group.The safety profile of the Lunsumio and Polivy combination therapy is consistent with the known safety of the individual investigational drugs, potentially allowing for use in outpatient and community settings. The incidence of cytokine release syndrome (CRS) events in the Lunsumio plus Polivy combination therapy was low, occurring in one in four patients, with less than 5% experiencing grade 2 or 3 CRS events. No immune effector cell-associated neurotoxicity syndrome events were reported. The incidence of grade 3-4 (58.5% vs. 57.8%) and grade 5 (5.2% vs. 6.3%) adverse events (AEs) was similar between the combination therapy and R-GemOx, with fewer AEs leading to treatment discontinuation in the Lunsumio plus Polivy combination therapy (2.2% vs. 4.7%). High-dose chemotherapy followed by stem cell transplantation has traditionally been the standard second-line treatment for relapsed/refractory LBCL patients. Although second-line therapies have made progress, diffuse large B-cell lymphoma (DLBCL) progresses rapidly, and many patients are unsuitable, intolerant, or unable to access the latest therapies. There is an urgent need for therapies that can be quickly accessed upon diagnosis of relapse to control the disease and improve long-term efficacy.Roche’s lymphoma portfolio is one of the most extensive in the industry, providing a unique and much-needed opportunity to combine regimens with different and complementary mechanisms of action. We are exploring the CD20xCD3 bispecific antibodies Lunsumio and Columvi (glofitamab), along with Polivy, to get closer to our goal of improving the lives of as many lymphoma patients as possible. This includes the Phase III STARGLO study [NCT04408638], which evaluates the efficacy and safety of Columvi combined with GemOx versus R-GemOx monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have previously received at least one line of treatment and are unsuitable for autologous stem cell transplantation, or have previously received two or more lines of treatment.
Three years ago, I wrote, “The CD3 bispecific antibody combined ADC has two advantages: first, it can dual-target and kill tumor cells, as the CD3 bispecific antibody can mobilize the body’s immune function, forming multiple mechanisms of action for killing. Second, the countless fragments formed after cell death can also be recognized by activated T cells, providing stronger combat capability, forming memory cells for sustained killing. This is analogous to PD-1 antibody combined ADC, but seems to surpass it, of course, it can also be considered to continue combining with PD-1/PD-L1 antibodies. The development of co-targeting ADCs and CD3 bispecific antibodies has also become a possibility. However, attention must be paid to the differences in epitope between the two to prevent competitive silencing, rendering one ineffective. As research progresses and understanding of various platforms deepens, too many possibilities have emerged before us. Therefore, there has never been such a thing as low-hanging fruit; science is always advancing, and understanding is always progressing.”
Now, Wuxi Biologics has further developed the CD3/DLL3 ADC, seemingly taking a step further.
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