Professor Song Yuqin: The new anti-CD20 monoclonal antibody otuzumab, innovative mechanism provides new treatment options for relapsed and refractory FL

Follicular lymphoma (FL) is one of the common indolent non-Hodgkin lymphomas (iNHL).
With the advancement of medical treatment, the survival rate of FL has been significantly improved, and the current median overall survival (OS) of FL Can reach more than 10 years
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Although the course of the disease is slow, FL is currently incurable and it is prone to relapse
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The humanized glycosylated new anti-CD20 monoclonal antibody, otuzumab, was approved in China in June this year, bringing new hope for meeting the treatment needs of Chinese FL patients
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This time Yimaitong specially invited Professor Song Yuqin from the Lymphoma Department of Peking University Cancer Hospital to share with you the difficulties in the treatment of relapsed and refractory FL, the innovative mechanism of the efficacy of otuzumab, and the clinical use of otuzumab in the treatment of relapsed and refractory FL.
Curative effect
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Desire for breakthroughs: incurable, repeated relapses, relapsed and refractory FL patients urgently need innovative treatments.
Most FL patients are difficult to be completely cured through existing treatment methods, and usually go through the process of "remission-relapse-remission-relapse".
Receiving the standard treatment of rituximab combined with chemotherapy + 2-year rituximab single-agent maintenance therapy, 49% of patients progressed, relapsed or died within 10 years, and as the number of treatment lines increased, the remission rate gradually decreased and remission The period gradually shortens, and the toxicity caused by multi-line treatment will gradually increase.
This is the difficulty in the treatment of relapsed and refractory FL
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There is no standard treatment plan for relapsed and refractory patients, but the treatment plan based on anti-CD20 monoclonal antibody is still the cornerstone of the treatment of B-cell lymphoma
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Riding the wind and breaking the waves: Otuzumab structural optimization and mechanism innovation, opening the way to break the game Although both are anti-CD20 mAbs, Otuzumab is the world's first humanized, glycosylated type II anti-CD20 mAb
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Unlike type I rituximab, which binds to the CD20 receptor, the binding method is different, and the tumor-killing mechanism is also different
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The CD20 binding sequence is different, and the unique epitope brings benefits to patients with rituximab resistance: Otuzumab has a unique CD20 antigen recognition epitope: 170ANPSEKNSP178 region, and the antigen recognition table of rituximab Bit 168 EPANPS173 only partially overlaps
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When the core epitope of rituximab (aspartic acid [N] at position 171) is mutated, the affinity of rituximab is greatly reduced and the CD20 antigen cannot be recognized normally
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The core epitope of otuzumab is closer to the C-terminal, so some patients with rituximab resistance/relapse can still benefit from the treatment of otuzumab
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Change in antigen binding mode, stronger DCD effect: The binding mode of otuzumab is that single molecule otuzumab binds to two CD20 dimer structures, without intermolecular cross-linking, and otuzumab-CD20 The complex does not enter the lipid raft, and this binding mode can reduce the endocytosis of the CD20-antibody complex
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In addition, due to different binding methods, otuzumab binds less to C1q, complement-dependent cytotoxicity (CDC) is weaker, DCD has a stronger effect, and activates the intracellular killing signal pathway
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Fc glycosylation engineering, activate immune effector cells, stronger ADCC effect: glycosylation engineering modification enables the Fc segment of otuzumab to more effectively interact with FcγRIII-expressing effector cells, increasing the ability of immune effector cell recruitment and Promote activation
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Otuzumab can induce a stronger ADCC effect in the in vitro test of human tumor cells, which is 35 times stronger than that of rituximab-induced antibody-dependent cell-mediated cytotoxicity and phagocytosis (ADCC/ADCP)
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Otuzumab is administered on days 1, 8, and 15 in the first cycle, and the target complete binding rate is faster: according to phase I and II PK studies, on the 8th and 15th day of the first cycle of otuzumab There are two loading doses (1000mg) per day, which can produce high target saturation faster
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As a result, otuzumab 1000mg, the first cycle 1, 8, 15 days of administration, reach the maximum target saturation faster
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It shines: Otuzumab has excellent efficacy in the treatment of relapsed and refractory FL.
The final analysis result of the GADOLIN study showed that the use of GB regimen in iNHL patients after rituximab resistance can be compared with B monotherapy.
Reduce the risk of disease progression or death by 43%, and have sustained and clinically significant progression-free survival (PFS) and OS benefits for patients
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In terms of safety, no new or unexpected safety signals of otuzumab have been found
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Figure A PFS and OS (INV assessment) in intention-to-treat patients (n=413) Figure B PFS and OS (INV assessment) in FL patients (n=335) based on the excellent efficacy and safety of the GADOLIN global phase III study Benefits, otuzumab has been recommended for the treatment of relapsed and refractory FL in the 2021 edition of the Chinese CSCO Lymphoma Diagnosis and Treatment Guidelines, and the treatment plan based on otuzumab has become a new choice for the treatment of relapsed and refractory FL
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"Follicular lymphoma (FL) is a common iNHL.
The disease progresses slowly, with a median survival of about 10 years.
Patients have limited access to drugs within 10 years.
How to use good medicines and avoid excessive Treatment, choosing the most appropriate individualized treatment plan for the patient, is a test of the clinician's overall strategic ability
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The
 GADOLIN study shows that rituximab-resistant FL patients or relapsed after treatment, the use of otuzumab is still effective , And there is a survival benefit (compared with bendamustine single agent), which may be derived from the innovative mechanism of action of otuzumab
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Otuzumab is the world's first humanized glycosylation modified type II anti-CD20 monoclonal antibody.
It has higher antibody stability, stronger ADCC and DCD effects, and faster complete target binding rate
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 With the recent successful listing of otuzumab in China, more Chinese patients with FL will be able to obtain a new choice of more efficient and safe treatment options, and otuzumab-based treatment options are becoming a new and unanimously recognized treatment for FL Choose
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In addition to the treatment of FL, the treatment plan based on otuzumab has now "full bloom" in the field of lymphoma treatment.
The FDA has approved otuzumab in combination with BTK inhibitors and BCL-2 inhibitors for initial use.
For the treatment of patients with chronic lymphocytic leukemia/small cell lymphoma (CLL/SLL), the 2021 NCCN guidelines recommend otuzumab combined with chemotherapy or no chemotherapy for the treatment of second-line and above marginal zone lymphoma (MZL).
The exploration in B-cell lymphomas such as mantle cell lymphoma (MCL) has also been laid out, and the prospects are worth looking forward to
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"Professor Song Yuqin, Deputy Director, Chief Physician, and Doctoral Supervisor, Lymphoma Department, Peking University Cancer Hospital, Director, Chinese Society of Clinical Oncology (CSCO), Secretary-General, Chinese Society of Clinical Oncology (CSCO) Anti-Lymphoma Alliance, Director, Beijing Anti-Cancer Association, Lymphhaematological Oncology Committee Member, Chinese Society of Geriatric Oncology, Vice Chairman, Lymphoma, Hematology and Tumor Professional Committee, Vice Chairman, Chinese Geriatric Health Association, Lymphoma Professional Committee, Standing Committee and Secretary, Beijing Medical Association, Oncology Professional Committee References: 1.
Mössner E, et al.
Blood2010;115:4393– 4022.
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Herter S, et al.
Mol CancerTher 2013;12:2031–423.
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Golay J, et al.
Blood2013;122:3482–91.
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Illidge T, et al.
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2015 Nov;41(9)784 -92.
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Lurie H Sehn, et al.
Blood (2019) 134 (Supplement_1): 2822.
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SEHN LH, et al.
Lancet Oncol, 2016, 17: 1081-1093.
7.
Chinese Society of Clinical Oncology (CSCO) Lymphoma Diagnosis and Treatment Guidelines 2021.
8 .
Otuzumab injection instructions.
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