All aspects of CD30 target: ADC is a hit, but red anti-double antibody has no fruit yet. CART research and development is fierce...

CD30 is a member of the tumor necrosis factor (TNF) receptor superfamily, which can promote cell proliferation or apoptosis by activating different signaling pathways.
It was used in 1982 as a monoclonal antibody for Hodgkin’s lymphoma (HL) cell line.
(MAb) was discovered, and was once considered an ideal target for disease treatment
.

In 2020, Verbutuximab for injection (Adcetris) was approved for marketing in China, and CD30 became famous
.

Recently, Adcetris was approved for the treatment of CD30-positive primary cutaneous anaplastic large cell lymphoma or mycosis fungoides that had previously received systemic treatment.

01, CD30

Research and development found that CD30 is closely related to cell proliferation and death.
The stimulation of CD30 molecules can induce receptor trimerization and signal transduction, which in turn activates the nuclear factor-κB (NFκB) pathway
.

At the same time, CD30 is also involved in the mitogen-activated protein kinase (MAPK) pathway (including ERK1 and ERK2), which plays an anti-apoptotic and pro-survival role in tumor cells

In healthy cells, CD30 is not expressed, but is low on the surface of normally activated T cells and B cells
.

On the surface of Hodgkin's lymphoma and anaplastic large cell lymphoma, CD30 is often highly expressed

Although CD30 has the characteristics of low expression in healthy cells and high expression in tumor cells, the performance of anti-CD30 drugs that enter clinical trials is not very satisfactory.
Clinically, anti-CD30 antibodies are used to target Hodgkin’s lymphoma (HL) and intermedium.
Degenerative large cell lymphoma (ALCL) has not shown a significant therapeutic effect
.

The first-generation anti-CD30 monoclonal antibodies, such as SGN-30 and MDX-060, have poor tumor inhibitory effects.

       02, CD30 ADC

       The trade name of Brentuximab Vedotin is Adcetris.
It was developed by Seattle Genetics.
In 2009, Seattle Genetics reached an agreement with Takeda Pharmaceuticals.
The latter obtained the commercialization rights of Adcetris in countries other than the United States and Canada.

.

Adcetris has a clinically effective rate of 73% and 86% for HL and ALCL, respectively.

       Adcetris is an antibody-conjugated drug (ADC) targeting CD30, which consists of three components: (1) Human-mouse chimeric monoclonal antibody Brentuximab targeting CD30; (2) Citrulline-valine random couple Linked dipeptide linker; (3) Small molecule drug MMAE (Auristatin E), DAR=4
.

       When Adcetris binds to the tumor cell membrane CD30 receptor, Adcetris is internalized into the lysosome mainly through clathrin-mediated endocytosis, and then the dipeptide is hydrolyzed and broken by protease, and finally MMAE binds to the cytoplasmic tubulin to block it.
The G2/M phase of the cell cycle causes cell death
.

Due to the use of cleavable Linker, MMAE can act on surrounding cells through the cell membrane and produce cytotoxic effects on CD30 non-positive tumor cells

       Adcetris was approved by the FDA in 2011 and approved by the NMPA in 2020
.

Judging from its market performance, Adcetris sales have been increasing steadily since it went public in 2011

       Only the F0002-ADC of Fudan Zhangjiang/Crosslinked Drugs has the domestic layout of CD30 ADC
.

F0002 consists of three parts: human-mouse chimeric anti-CD30 monoclonal antibody, thioether linker (MCC) and DM1

       03, CD30 double antibody

       There is currently no drug approved for CD30 double antibody, and Affimed's AFM13 is the top clinical one.
At present, Hodgkin's lymphoma and T-cell lymphoma are in clinical phase II
.

       AFM13 is a tetravalent tandem CD16A×CD30 double antibody with a molecular weight of 100KD
.
CD16A is the Fc receptor on NK cells, which can mediate IgG1 antibodies to kill tumor cells through ADCC.
Usually CD16A has two subtypes, including 158V and 158F.
Among them, the binding ability of 158F and natural IgG1-Fc is weak.
Defucosylation enhances ADCC effect
.

       AFM13 can mediate the specific and selective killing of CD30-positive cells by macrophages and NK cells, that is, it can kill tumors through ADCC and ADCP
.
At the 2021AACR annual meeting, the Phase I trial showed that the objective response rate (ORR) of AFM13 for the treatment of relapsed/refractory CD30-positive Hodgkin’s lymphoma reached 100%
.
In the experiment, the tumors of 4 patients all achieved remission, including 2 cases of CR and 2 cases of PR
.
In terms of safety, no cytokine release syndrome, neurotoxicity syndrome, or graft-versus-host disease was observed
.

       The study also found that after binding to NK cells, AFM13 remains on the surface of NK cells, making it anti-CD30-positive cells-Karpas299 CAR characteristics
.
In addition, in the CD30-positive T-cell lymphoma xenograft mouse model in vivo, CAR cbNK cells combined with AFM13 showed enhanced anti-tumor activity
.

       04, CD30 CART

       CART cell therapy is currently one of the hottest research directions in the field of tumor cell immunotherapy.
It is an immunotherapy that kills cancer cells through autoimmune cells.
The current clinical practice of CD19 CART has achieved remarkable results
.
But for patients with lymphoma, CD19 is not expressed on the surface of all lymphoma cells, so scientists turned their attention to CD30
.
Compared with antibody drugs, CD30 CART therapy is not prone to drug resistance, or is expected to provide continuous treatment options for cancer patients
.

       At present, the domestic companies that have deployed CD30 CART cell therapy research include Eucardi, Porida and Imming Cell
.

       In May 2019, Shanghai Ucardi Biomedical Technology Co.
, Ltd.
CD30 CAR-T obtained a patent authorization from the State Intellectual Property Office, becoming the first company in China to obtain a CD30 CAR-T invention patent
.
In April 2020, Boruida Bio-targeted CD30 chimeric antigen receptor gene-modified autologous T cell injection (BRD-01) was approved clinically for the treatment of CD30+ relapsed/refractory hematological tumors aged 18 to 70 , Is the first clinically approved CAR-T cell therapy targeting CD30 in China
.
Imming Cell has taken the lead in the world to carry out clinical research on CD30 CAR-T cell therapy for the treatment or adjuvant treatment of Hodgkin’s lymphoma and anaplastic large cell lymphoma or other CD30-positive tumors.
The non-registered clinical trials that have been carried out have proved that, Its effective response rate is 92%, and the overall CR rate has reached the industry-leading level
.