Guide
The opening of every unknown world has been bravely foreseen by pioneers; Every journey of stealth in the dark of night, there are lighters fearlessly leading the way. The series of reports on "Solving the Problem of Star Solutions - Unlocking New Standards for DLBCL Cure" digs deep into the difficult problems in the treatment of diffuse large B-cell lymphoma (DLBCL) and explores the unmet needs of the clinic; Combined with clinical research and real-world treatment experience at home and abroad, we will jointly explore new standards for accurate diagnosis and treatment of DLBCL. Polatuzumab Vedotin (Pola) became Pole Star, and under the guidance of the field leaders, helped optimize diagnosis and treatment strategies in order to improve the survival of DLBCL patients in China.
The "Pola Three Offensive Weapons" series of articles analyzed Pola's payload drug MMAE in the last period, MMAE can enter nearby tumor cells through the bystander effect, repeatedly and continuously kill tumor cells, and let us see the dawn of overcoming tumor heterogeneity. Starting from the CD79b target, this issue will continue to explore the mystery of Pola's treatment of DLBCL.
This issue is a question
Targets are critical to ADCs, how do you choose between a wide range of targets when designing a hematologic tumor ADC drug? Based on the target expression level may affect ADC efficacy, ADCs generally require target detection to guide clinical applications, do all ADC drugs require target detection? In recent years, ADC drug research has become more and more popular, what is the special secret of the CD79b target selected in the development and the drug Pola that targets CD79b?
Star solution expert
ADC targets are difficult to choose, and many problems need to be solved
The use of small molecule chemotherapy drugs is greatly limited because serious adverse reactions will limit the dose of the drug, thus limiting the treatment window. ADCs target aggressive cytotoxic drugs to target cancer cells, thereby providing a broader therapeutic window, limiting the occurrence of off-target effects[1], combining the selectivity of targeted therapy with the cytotoxic effects of chemotherapy, and may alter tumor treatment strategies by improving efficacy, improved safety, or tolerance [2,3] towards more precise immunotherapy.
Figure 1 Comparison of treatment windows of small molecule chemotherapy drugs and ADCs
In the process of ADC drug development, the choice of target is the key to ADC drug development. Exploring the therapeutic targets of blood tumors and selecting the ideal targets of ADC drugs is a difficult problem that researchers have been working hard to break through. In the era of immunochemotherapy, CD20 as the star target of DLBCL is well known by many hematologists, although CD79b is similar to CD20 in the differentiation and expression stage of B cells, but there are very few drugs targeting CD79b at present, why did Pola, the world's first ADC drug for the treatment of DLBCL, choose to target CD79b to build a "magic bullet", and did not choose CD19, CD22 and other popular research targets and mature CD20 targets, what is the special secret behind it? Most of the previous globally available anti-tumor ADC drugs require target detection to guide clinical applications, do all ADC drugs need target detection to guide?
Layer by layer, the CD79b target stands out
In addition to the well-known CD20 targets, there are many targets that are expressed only on B cell and B cell tumors, and researchers have explored these targets to varying degrees in recent years. In the early stages of Pola's development, researchers first tested the efficacy and safety of ADCs on CD19, CD20, CD21, CD22, CD72, CD79b, CD180 and other targets in animal models of tumor transplantation [4]. It was found that most targets were only effective for enzyme-lysable linker-drugs, while CD22 and CD79b were more of interest because they were both effective against ADCs of enzyme-lysable or non-lysable connectons [4].
Fig. 2 Efficacy curve of 7 targets
Studies of antitumor activity in vitro have demonstrated that the efficacy of ADCs targeted with MC-vc-MMAE that targets CD22 and CD79b is not affected by target expression levels, and the population will be treated more extensively [5].
Fig. 3 Relationship between efficacy of anti-CD22 ADC and anti-CD79b ADC and target expression level
Further studies have shown that half of the effective doses against CD79b-vc-MMAE (Pola) are lower than anti-CD22-vc-MMAE (Pina),[6] meaning that Pola may have a wider therapeutic window.
Figure 4 Efficacy response of Pina and Pola at different doses
The Phase II ROMULUS study also suggested that Pola was more effective, with a longer duration of remission (DOR) than Pina and a better benefit-risk profile, with a lower incidence of Pola than Pola in both Grade 5 adverse events (AE) and severe adverse events (SAE). After layers of screening, CD79b became the preferred treatment target for non-Hodgkin lymphoma (NHL).
Fig. 5 Pina and Pola combined with rituximab for the treatment of R/ R DLBCL and FL DOR
Figure 6 AE cases of Pola and Pina combined with rituximab in the treatment of R/R DLBCL
Demystify the CD79b target and target THE CD79b ADC Pola has unlimited prospects
CD79 is a heterodimer molecule involved in signal transduction in the components of the B cell receptor (BCR), consisting of two peptide chains, CD79a and CD79b (Igα and Igβ, respectively), with high specificity of the B cell lineage, high expression on a variety of B cell NHL and chronic lymphocytic leukemia B cells, and has a broad mechanism of action to kill B cell tumors[8]. At the same time, preclinical studies have also verified that CD79b as a binding site is more efficient than targeting CD79a[9], so CD79b is an ideal therapeutic target for the mechanism of action of ADC, which can be transported to the protease-rich lysosomal-like compartment through delicate endocytosis, thereby effectively delivering the loaded drug and causing targeted cytotoxic killing [10].
Figure 7 CD79b is the BCR component
Both in vitro and in vivo transplant tumor models suggested that the cause of vc-MMAE ADC drug (Pola) resistance targeting CD79b did not come from the downregulation of the target or the internalization efficiency of the target, and the drug-resistant transplant tumor could still maintain the expression level of the target[11]. Genetic analysis of the oligonucleotide microarray technique for transplant tumors showed that only the P-gp gene was upregulated by more than one order of magnitude in the resistant strain[11], and the expression level was about 100 times that of the parent cell line, which was also verified in the flow cytometry analysis. The primary driver of acquired drug resistance is P-gp overexpression, which is thought to be associated with chemotherapy resistance [11].
Figure 8 The expression levels of CD22 and CD79b on the surface of tumor cells were similar in the original and drug-resistant strains by flow cytometry
Figure 9 P-gp expression levels on the surface of drug-resistant cell lines measured by flow cytometry. The original strain is almost not expressed, and the resistant strain is highly expressive
With the unique advantage of precision and potency, not being resistant due to target downregulation, the GO29365 study, a clinical trial of CD79b-targeted ADC Pola in relapsed refractory (R/R) DLBCL populations that are not suitable for transplantation, showed extraordinary results, with the Pola-BR group significantly improving the patient's complete response (CR) rate (40.0% vs 17.5%); P=0.026) and the best CR rate (57.5% vs 20%)[12,13]. After a median follow-up of 22.3 months, Pola-BR further extended progression-free survival (PFS, 9.5 vs 3.7 months; P<0.001) and overall survival (OS, 12.4 months vs 4.7 months; P=0.002), and reduces the risk of death by 58% [12,13].
In addition, a randomized controlled cohort biomarker analysis showed that neither tumor remission nor PFS/OS benefit was associated with CD79b expression levels (P=0.69), and the efficacy of Pola was not affected by CD79b expression levels [12]. CD79b expression level analysis showed that CD79b expression was detectable by immunohistochemistry (IHC) in 96.4 percent of patients, and parallel RNA testing from IHC-negative samples in three other patients also showed positive CD79b expression, suggesting that IHC needs to pay attention to detection sensitivity or false-negativeness [12].
Figure 10 Analysis of PFS, OS, and CD79b protein expression in patients
This finding was also validated in a Phase IB/II study of Pola treating patients with primary DLBCL, GO29044 [14]. Exploratory biomarker analysis showed that tumor samples from all patients were positive for IHC and RNA CD79b, and there was no correlation between tumor lesion reduction and PFS and CD79b expression levels [14].
Figure 11 Analysis of tumor remission and PFS and CD79b protein expression levels in patients
Based on the above study data, Pola treatment of DLBCL does not appear to require CD79b target detection to guide clinical applications, and DLBCL patients should not be excluded from Pola treatment because of low CD79b target expression. With its advantages of good safety, considerable efficacy, and unaffected by target expression levels, Pola is expected to play a pivotal role in the first-line and posterior treatment of DLBCL.
Star Interpretation Quotes
Cancer Hospital of Tianjin Medical University
Professor Zhang Huilai
ADC drugs have made considerable progress in the past 10 years, researchers pay special attention to the selection of targets, CD79b is the preferred target for blood tumors obtained after layers of screening.
Since the surface of tumor cells often specifically expresses some disease diagnostic antigens, or the antigen expression level has a limiting effect on the binding ability and therapeutic ability of antibodies, many ADC drugs in the past have required target detection to guide clinical applications. Two Phase IB/II clinical studies, GO29365 and GO29044, showed that IHC or RNA analysis was CD79b positive in patients who were not screened as the admission criteria, and Pola efficacy was not related to the target expression level, suggesting that their later clinical development did not require further target detection of patients to screen patients, and it is believed that patients in future clinical practice regardless of CD79b expression level are likely to benefit from Pola treatment regimens. It is expected that the launch of Pola will bring accessible treatment options to China's DLBCL and benefit more Chinese patients.
Affiliated Cancer Hospital of Fudan University
Professor Tao Rong
ADC drugs combine the selectivity of targeted therapy with the cytotoxic effects of chemotherapy, leading patients towards more precise immunotherapy. Cd79b's effectiveness in both lysable and non-lysable connectors and its better benefit-risk profile set it apart from its competitors during ADC drug development with a wide range of targets in B-cell tumors.
ADC Pola, which targets CD79b, is a rising star for its leading molecular design and solid clinical exploration. With the good safety and considerable efficacy shown in the GO29365 study and the global phase III confirmatory POLARIX study, as well as the advantage that the clinical treatment effect is not affected by the target expression level, Pola has broad applications and further exploration prospects in the field of hematological tumors.
"Magic Bullet" Pola boosts the DLBCL treatment station to a new height, MMAE, CD79b target, crackable connector behind the three major offensive weapons in turn, the next issue is about to unveil the mystery of the cleavable connector, not to be seen!
Zhang Huilai Professor
- Doctor of Oncology, Chief Physician, Doctoral Supervisor
- He is currently the director of the Department of Lymphoma Internal Medicine, Cancer Hospital of Tianjin Medical University
- His research interests include molecular diagnosis and individualized treatment of malignant lymphoma
- Vice Chairman of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association
- Member of the Standing Committee of the Lymphoma Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
- Member of the Lymphoma Group of the Oncology Branch of the Chinese Medical Association
- Vice Chairman of the Internal Oncology Branch of the Chinese Medical Promotion Association
- Vice Chairman of the Lymphatic Disease Committee of the Chinese Medical Education Association
- Vice Chairman of the Lymphoma Professional Committee of the Chinese Geriatric Health Care Association
- Chairman of the Tumor Clinical Chemotherapy Committee of Tianjin Anti-Cancer Association
- Vice Chairman of Tianjin Hematology Quality Control Center
- Vice President of Hematologist Branch of Tianjin Medical Doctor Association
- He has won 1 second prize and 3 third prizes of Tianjin Science and Technology Progress Award, and has presided over and participated in a number of National Natural Science Foundation projects and provincial and ministerial scientific research projects. Currently, he is the deputy editor of "Cancer Pharmacy", "Chinese Journal of Hematology", "Leukemia / Lymphoma", "Chinese Oncology Clinic", "Hematological Oncology", "Blood Research", "Discover Oncology" and other domestic and foreign journals and magazines, with the first or corresponding author in Blood, J Exp Med, JITC, Leukemia, CTM, AJH, BJH, Blood Adv, Front Oncol, Hematol Oncol, Int J Cancer and other international professional magazines, as well as the China series of magazines, national core journals published more than 70 papers. Won the 4th "Famous Doctor of the Country , Excellent Style" Award.
Professor Tao Rong
- Ph.D., Chief Physician
- Director of the Department of Lymphoma, Fudan University Affiliated Cancer Hospital
- Member of Shanghai Hematology Specialist Committee, Deputy Leader of Lymphoma Group
- Member of hematology branch of Shanghai Medical Doctor Association
- Member of the Hematology Branch of Shanghai Anti-Cancer Association
- Member of Shanghai Clinical Research Ethics Committee
- Standing Committee Member of Translational Medicine Special Committee of China Medical Education Association
- He is mainly engaged in basic and clinical research on lymphoma, and has in-depth clinical research on the diagnosis and treatment of NK/T cell lymphoma, peripheral T cell lymphoma, and high-risk diffuse large B-cell lymphoma.
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Editors: Evelyn, Chole
Typography: moly
Execution: Wenting