Mizuxing Xie Xie Zhu Jun and Guo Ye: Pola's Three Great Weapons (1) - MMAE Bystander Effect Laying a Mechanistic Basis for Breaking Through the Heterogeneity of DLBCL

Every unknown world is opened, and there are pioneers who bravely foresee; every journey of sneaking in the dark night, there are those who light the way fearlessly

Standard immunochemotherapy containing rituximab is usually effective in DLBCL patients, but due to the "high degree of heterogeneity" in the pathological mechanism of DLBCL, the clinical manifestations, treatment and long-term outcomes of patients vary greatly, and nearly half of the patients fail the standard.

Lymphoma is a heterogeneous group of hematological malignancies caused by the malignant transformation of lymphocytes.

Figure 1 Schematic diagram of the development and differentiation of B cells

DLBCLs are aggressive tumors derived from mature B cells that, in addition to lymph nodes, frequently involve extranodal sites (including kidney, adrenal gland, brain, bone, and other soft tissues)

Figure 2 National Cancer Research Center "LymphGen 7 classification" and prevalence in the general population

As an aggressive NHL, DLBCL has a relatively short natural history, but a certain percentage of patients can be cured with appropriate treatment, making it a group of curable lymphomas

With the in-depth understanding of the mechanism by researchers and the iterative upgrade of technology, antibody-drug conjugates (ADCs), known as "magic bullets", have become a rising star among new anti-tumor drugs

Figure 3 ADC mechanism of action

When the released payload is osmotic or transmembrane, a "bystander killing effect" can be induced to enhance the efficacy of the ADC
.

The "bystander effect", in which a cell-permeable payload diffuses from a cell expressing a target antigen to adjacent cells to exert cytotoxicity regardless of the expression of the target antigen in adjacent cells ^[4,5] , thus disrupts tumor heterogeneity.
qualitative dilemma
.

Figure 4 Bystander effect

At present, there are many studies on the bystander effect in solid tumors, especially breast cancer, represented by ADC Trastuzumab deruxtecan (T-DXd) targeting HER2 and ADC Sacituzumab govitecan (IMMU-132) targeting TROP-2, surpassing the Targeted drugs focus on the limitations of traditional molecular typing.
Regardless of patient type and the expression level of corresponding targets, breakthrough efficacy data has been achieved, which is inseparable from the payload that can exert the "bystander effect".
The advent of these ADCs is expected to rewrite the traditional treatment paradigm for breast cancer in the future
.

In hematological tumors, ADCs are also constantly updated and iterated.
The ADC Pola targeting CD79b is currently the only third-generation ADC approved in lymphoma, and the cytotoxic drug it carries is the most commonly used drug in ADC development.
Methylauristatin E (MMAE), because the free MMAE surface is electrically neutral and released through a cleavable linker, can more easily cross the cell membrane to exert a bystander effect
.

Compared with first- and second-generation ADCs, the therapeutic window of Pola continues to expand, including the continuous increase in the upper limit of dose-limiting toxicity (DLT), and the onset of the dose level can be lower, and the payload drug that exerts the "bystander effect" can be repeated.
, Sustained killing of tumor cells is one of the potential mechanisms for the expansion of the therapeutic window
.

The pharmacokinetic data of Pola shows that the highest concentration of free MMAE does not exceed 1/100 of the bound state, and the half-life is also shorter than that of the bound ADC drug and the free antibody; periodic injections at a therapeutic dose of 1.
8 or 2.
4 mg/kg The plasma concentration of free MMAE reached a peak in the first cycle, and the concentration continued to decrease significantly in the third and sixth cycles, indicating that there was no plasma accumulation, and there was no significant impact on clinical safety, suggesting that Pola was in Phase II and/or Phase III clinical trials.
The test does not need to monitor free MMAE ^[6]
.

In conclusion, Pola's bystander effect not only plays an important role in addressing the high heterogeneity of DLBCL, but also achieves the best possible balance between maintaining a manageable safety profile and enhancing efficacy
.

In terms of clinical efficacy, the Pola-BR group significantly improved the PFS, OS, and CR rates of R/R DLBCL patients by nearly 3 times compared with the BR group, and reduced the risk of death by up to 58% ^[7]
.

In patients with R/R DLBCL who have received a median number of previous lines of therapy ≥3L, the CR rates (range 40%-58%) of Pola-BR and the 4 global marketed CAR-T products are similar or higher (non- head-to-head comparison)
.

Based on the above GO29365 study results, Pola has been approved by the US FDA for accelerated treatment of R/R DLBCL in June 2019, becoming the world's first ADC approved for the treatment of DLBCL
.

Figure 5 GO29365 research results

*BR: bendamustine combined with rituximab; PFS: progression-free survival; OS: overall survival; CR: complete response

Throughout the 25-year history of R-CHOP+X exploration, many new targeted drugs have failed miserably in the pursuit of higher cure rates
.

Excitingly, on the basis of ensuring safety, the POLARIX study ^[8] confirmed that the Pola-R-CHP regimen is superior to the R-CHOP standard treatment regimen.
This study is also the first time to surpass the classic R-CHOP in an international phase III controlled study.
Exploration of the program
.

The Asian subgroup analysis of the POLARIX study updated by EHA/ASCO this year ^[9] showed that, with a median follow-up of 24.
2 months, the PFS of the Pola-R-CHP group was better than that of the R-CHOP group, and the relative risk of disease progression, recurrence or death was reduced by 36% (HR 0.
64; 95%CI 0.
40-1.
03), comparable to the PFS benefit in the global population
.

This dazzling data undoubtedly reflects the light that the "North Star" cannot hide again, and at the same time increases the confidence in the field of lymphoma to overcome the heterogeneity of lymphoma through "magic bullets"
.

Figure 6 The results of the POLARIX study in the Asian population

Peking University Cancer Hospital

Professor Zhu Jun

Due to the high clinical and genetic heterogeneity of DLBCL, there are marked differences in response to standard therapy among different patients
.

Pola is an ADC conjugated with anti-CD79b monoclonal antibody and MMAE.
The CD79b antigen is widely expressed on the surface of B lymphocytes and mediates the rapid endocytosis of the antibody.
Its payload drug, MMAE, is electrically neutral on the surface and released through a cleavable linker.
Through the bystander effect, it can continue to enter adjacent tumor cells to achieve repeated and sustained killing of tumor cells, which allows us to see the dawn of conquering tumor heterogeneity
.

At present, Pola has shown significant survival benefits in both newly treated and R/R DLBCL patients.
It is hoped that in the near future, Pola will become an accessible treatment option for Chinese DLBCL patients and bring more benefits to more Chinese patients.

.

Dongfang Hospital Affiliated to Tongji University

Professor Guo Ye

The origin of ADC can be traced back to the early 20th century, when Paul Ehrlich of Germany first proposed the concept of selectively delivering cytotoxic drugs to tumors through targeting agents
.

More powerful than targeting and more precise than chemotherapy is the ideal pursued by every ADC drug.
In the past ten years, ADCs have been improved through the selection of optimized cytotoxic drugs, antibody engineering technology and bioconjugation technology
.

In solid tumors, ADCs targeting HER2 and TROP-2 have achieved breakthrough efficacy data, which is expected to rewrite the traditional treatment mode of breast cancer in the future; The outstanding performance in the POLARIX study sets a new benchmark in the treatment of DLBCL
.

I hope more ADCs will be successful in the future, making magic bullets more accurate and efficient
.

Professor Zhu Jun

• Secretary of the Party Committee of Peking University Cancer Hospital

• Chief of Internal Medicine, Chief of Lymphoma Department

• Executive Director of the Council of the Chinese Society of Clinical Oncology (CSCO)

• Vice Chairman of Beijing Heathco Clinical Oncology Research Foundation

• Chairman of the CSCO Lymphoma Expert Committee

• Vice President of Beijing Anti-Cancer Association

• President of Beijing Cancer Rehabilitation Association

• Standing Committee Member of Oncology Branch of Chinese Medical Association

• Member of the National Health Commission Capacity Building and Continuing Education Oncology Expert Committee Leader of the Hematology Oncology Group

Professor Guo Ye

• Chief Physician, Doctoral Supervisor

• Dongfang Hospital Affiliated to Tongji University

• Deputy Director of the Department of Oncology and Director of the Phase I Clinical Center

• Deputy Secretary General of Chinese Society of Clinical Oncology

• Chairman of the Head and Neck Cancer Professional Committee of the Chinese Society of Clinical Oncology

• Vice Chairman of Thyroid Cancer Professional Committee of Chinese Society of Clinical Oncology

• Vice Chairman of the Head and Neck Cancer Professional Committee of the Chinese Medical Doctor Association

• Vice Chairman of Lymphoma Professional Committee of China Elderly Health Care Association

• Member of the Standing Committee of the Lymphoma Alliance of the Chinese Society of Clinical Oncology

• Vice Chairman of the Youth Committee of the Cancer Chemotherapy Professional Committee of the Chinese Anti-Cancer Association

• Member of Head and Neck Cancer Professional Committee of China Anti-Cancer Association

• Member of the Nasopharyngeal Cancer Professional Committee of the Chinese Anti-Cancer Association

• Member of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association

• Vice Chairman of Head and Neck Cancer Professional Committee of Shanghai Anti-Cancer Association

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Star Solutions for Mistakes | Prof.
Zhao Weili and Prof.
Liu Yanyan: How to break through the R/R DLBCL Mistakes? Chinese and foreign experience unlocks new solutions

Editor: Evelyn

Reviewer: Janet

Typesetting: siqili

Execute: moly

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