Background
After more than 30 years of development, antibody drugs have become one of the most important branches in the field of biopharmaceuticals, with sales increasing year by year. The development of various immunotherapies, such as immune checkpoint inhibitors (ICIs) and T-cell-redirecting bispecifics (TCBS), has brought subversive effects to many diseases treatment effect. Although immunotherapy prolongs the survival time of patients with various types of tumors, systemic immune activation effects also occur in healthy tissues, leading to immune-related adverse events (irAES). These toxic and side effects accompanied by antibody drugs often severely affect the application of drugs, which are mainly related to the binding of antibody drugs to the drug-targeted antigen expressed by certain healthy tissue cells (On target). In response to the side effects caused by the healthy tissue On target of antibody drugs, Probody improves safety by improving the specificity of diseased tissues.
The core idea of Probody technology is actually “prodrug” (“prodrug”), that is a kind of drugs that do not function in the initial state, and only after the body’s metabolism is transformed into an active form or reach a specific site can it exert a therapeutic effect.
Composition of Probody therapy
CytomX refers to antibody drugs using Probody technology as Probody therapy. Probody therapy is an antibody prodrug technology developed by CytomX Therapeutics that can overcome immune-related adverse events (irAEs). It consists of three modules (see Figure 1):
1) Anti-tumor monoclonal IgG antibodies or fragments of variable regions,
2) Masking peptide connected to the N-terminus of the light chain,
3) Cleavable linker protease
In healthy tissues, the Probody antibody remains basically intact, and the masking peptide prevents the antibody from binding to the target, avoiding the side effects of off-tumor. When Probody reaches the tumor microenvironment, the tumor-associated protease cleaves the substrate linker, removes the masking peptide, and the antibody binds to the target antigen.
Development of antibody drugs based on Probody technology
1. CX-072 (Target PD-L1)
CX-072 is an early project based on Probody technology. In 2017, a clinical study was carried out to evaluate the tolerability and anti-tumor activity of CX-072 monotherapy or combination therapy, and to treat patients with advanced unresectable solid tumors or lymphomas. It is expected to end by the end of 2021. CX-072 is now starting another phase 2 clinical trial (PROCLAIM-CX-072-002 NCT03993379) for previously untreated solid tumors, solid tumors that relapse after checkpoint inhibitor treatment, and those that have progressed during or after platinum treatment Solid tumors, or neoadjuvant therapy. Results are expected by the end of 2023.
2. CX-2029 (target CD71)
Carried out the PROCLAIM-CX-2029 clinical study (NCT03543813) for metastatic or locally advanced unresectable solid tumors (head and neck, non-small cell lung cancer, pancreas) or diffuse large B-cell lymphoma. The results are expected by the end of 2022.
3. BMS-986249 (target CTLA-4)
Authorized to BMS, phase 1/2 clinical study CA030-001 (NCT03369223) is being carried out to treat advanced solid tumors. Preliminary results are expected in 2022.
4. CX-2009 (target CD166)
CD166 (Activated Leukocyte Adhesion Molecule) is a transmembrane protein that acts as a connection adhesion molecule to promote cell migration, differentiation and hematopoiesis. It is widely expressed in dividing cells, normal cells and malignant cells. (See picture 2)
For CX-2009, the DPR is 4, and the payload is DM4. dm4-related toxicity, including ocular, neuropathy and liver toxicity. CX-2009 is carrying out a phase 1/2 clinical study, PROCLAIM-CX-2009 (NCT03149549), for the treatment of metastatic or locally advanced unresectable solid tumors (breast, NSCLC, prostate, ovary, endometrium, head and neck) , Cholangiocarcinoma). Results are expected by the end of 2021.
Current challenges and problems
The difficulties of the current Probody technology are as follow. First, the release of the drug in the tumor microenvironment is uncontrollable; second, Pro-ADC cannot perfectly solve the on target toxicity. Its shielding and binding ability is too strong, and the drug effect will be lost. It can only be done appropriately attenuate.
Therefore, the card dilemma that Probody technology is easy to encounter is that as soon as it is effective, there will be toxicity. There are two kinds of toxicity, one is on target toxicity, and the other is payload toxicity. From this point of view, the current Probody technology is difficult to make a big difference in curative effect, and further research by scientific researchers is needed.
Summary
In principle, probody technology can overcome the side effects of off-tumor and reduce the occurrence of irAEs. There are many drugs are currently undergoing clinical trials. CX-072 has more data and the preliminary results are positive. However, the overall sample size is still relatively small, and further large-sample clinical studies are needed to verify its effectiveness and the overall improvement in the incidence of irAES.
Reference
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