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CAR-T Cell Therapy Improved to Surprise More Cancer Patients

After decades of efforts, researchers have finally acquired the chimeric antigen receptor T cells based on monoclonal antibodies in the cancer immunotherapy field. CAR T cells contain a specific antibody variable region and a T cell activated motif that is genetically modified to respond to target cells expressing a particular antigen. For decades, developers have struggled to explore ways to construct different antigen-specific complexes and fuse constructs to T cells.

However, the problem is that these CAR T cells activate T cells in large quantities, releasing a large number of cytokines and forming a cytokine storm, which will bring about a large toxic effect. Fortunately, this toxic side effect is increasingly controllable. Unlike other tumor immunotherapies, the anti-tumor effect of CAR T cells is sustained and does not require continuous administration because CAR T cells divide and the resulting daughter cells are also tumor specific.

Compared to treating blood tumors, CAR-T cell therapy for solid tumors is not that simple. It is necessary to send modified T cells into specific cells by means of CAR T target, and suitable molecular targets are currently lacking. In addition, the dense matrix in the interstitial tissue inhibits immune cell infiltration.

But we have reason to be optimistic. With the discovery of new antigens produced by tumor-specific mutations and the recognition of a new class of glycosylated Tn/sTN epitopes, there have been encouraging advances in the study of new targets. The Tn/sTN epitope formed by sialylation of the simplest O-glycan structure Tn antigen is widely expressed in tumor cells, and CARs specific for certain epitopes have demonstrated surprising antitumor activity in some studies.

Innovative solutions for CAR-T cell therapy are being designed and developed to reduce the likelihood of adverse side effects and improve the timing of CAR-T cell activation. Several different types of suicide genes or safety switches have been incorporated into CAR T design, including manipulation of CAR-T cell apoptosis via the induced caspase-9 system, and its safety is being evaluated in clinical trials.

Kite's T cell receptor chimeric T cell (TCR T) therapy MAGE A3/A6 is currently in clinical phase 2, with the indication of solid tumor. The indications for the TCR-T therapy JTCR016 of the US biopharmaceutical Juno include WT1-positive non-small cell lung cancer and mesothelioma, which have also entered the phase 1/2 clinical stage. In addition, companies that use CAR-T cell therapy to treat solid tumors include Houston-based Bellicum Pharmaceuticals, which launched Phase 1 clinical trials for pancreatic cancer at the end of 2016.

Researchers are working to assess the safety and efficacy of CAR-T cell therapy in combination with checkpoint inhibitors or other targeted therapies. Initial trial results show that some combination therapies have the potential to significantly improve the patient's treatment. For example, in combination with the CRISPR/Cas9 gene editing technology, CAR-T cell therapy has been greatly improved. Selective deletion of negative regulatory genes using CRISPR/Cas9 gene editing technology can increase CAR-T cell survival and anti-tumor activity, and CRISPR/Cas9 gene editing technology is also used to create CAR-T lacking endogenous T cell receptors. Cells, to reduce the likelihood of graft-versus-host disease, give greater potential to CAR-T cell therapy.

More and more companies have joined the ranks of cancer immunotherapy research and development. The results accumulated over the years have witnessed the first wave of CAR-T cell therapy development. CAR-T cell therapy may make even more progress in research and development in the next decade. Especially in the attempt of tumor immunocombination therapy, CAR T technology volatilizes its unique role. As a hot tumor immunotherapy, the ever-improving CAR-T cell therapy is bound to surprise more and more cancer patients.

About

As a global company, Creative Biolabs has more than 200 talented and well-trained scientists located in different continents working closely with partners from the entire world to develop and produce medicines of tomorrow. Specifically, the established leading experts in TCR and CAR T&NK cell immune therapy development offer the one-stop custom services that cover the entire new drug development pipeline, and an exclusive line of ready-to-use TCR and CAR T&NK cell construction products, such as virus packaging, purification, expansion and titer determination kits. Furthermore, a unique unparalleled CAR construction and production platform has been built up for all four CAR generations.

 

Tags: CAR T technology

Overview on Antibody-drug Conjugates Development

Since the 20th century, medical scientists represented by Paul Ehrlich, the father of chemotherapy, have been searching for such a "magic bullet" that distinguishes between pathogens and normal cells. Since the beginning of the new century, more and more people believe that antibody-drug conjugate (ADC) is the answer that has long been sought.

The ADC is made by attaching a cytotoxic small molecule drug to a monoclonal antibody via a chemical antibody drug conjugate linker, which combines the targeting of antibodies with the lethality of small molecule chemicals.

During the whole process, the antibody is equivalent to the missile's "navigation system", which guides it to find the tumor cells. The small molecule cytotoxic drugs coupled with the antibody are equivalent to the missile's "warhead" and kill the tumor cells. Antibody drug conjugates use the targeting of monoclonal antibodies to target small molecule drugs to pathogens such as tumors, avoiding normal cells, thereby minimizing the damage of drugs to normal cells.

The development of antibody conjugation is much more complicated than common drugs including target screening, selection of small molecule chemical drug warheads, design and optimization of coupled molecules, and antibody selection.

ADC drug is mainly used for anti-tumor, so the ideal target antigen should be expressed at a high level on the surface of tumor cells, with little or no expression in normal cell tissues. Some of the tumor targets currently screened in clinical trials are expressed only in certain types of tumor cells, and many targets are expressed in most types of tumor cells.

Secondly, after binding the antibody to the selected antigen, it can be effectively internalized, facilitating the entry of the ADC into the cell and killing the target cell. However, some studies have shown that in some cases, even if the antibody drug complex and the target are combined, no internalization into the cell can exert a bystander effect and kill the tumor cells.

Selection of drug "warhead"

Currently, antibody drug complexes have a limited number of small molecule chemicals to choose from, some of which are microtubules inhibitors that inhibit mitosis; the other are DNA-damaging agents.

Most of the small molecule cytotoxic drugs used in ADCs are hydrophobic, preventing antibody aggregation, thereby prolonging the shelf life of the drug, increasing the residence time in blood tissue, and enhancing the efficacy of the ADC.

Since only a small portion of the antibody can effectively enter the tumor site after entering the body, the drug needs to have an efficient and sensitive killing effect on the target cell. Common drug warheads include: Auristatins, Tubulysins, Calicheamicins, Duocarmycins, Benzodiazepines, Camptothecin analogues, Doxorubicin.

Antibody selection and optimization

Because the ADC stays in the environment before entering the cell, it is often tissue blood. In clinical trials, the requirement for ADC drugs is to stay in the blood for as long as possible before exposure to pathogenic cells. The antibody drug complex in this process should be in a state of being stable, not decomposing, and not being cleared by the human immune system.

This requires that the selected antibodies need to have relatively low immunogenicity, long half-life, and high stability. The traditional antibody protein subtypes mainly include IG1, IG2, IG3, and IG4, among which, since the half-life of IG3 in tissue blood is only other 1/3 of the antibody type, so clinically IG3 is generally not selected as an ADC drug.

Compared with the development of common drugs, antibody drug conjugates require more research and development investment, but because of the great side effects of ordinary chemotherapy, the body is rapidly weakened during cancer treatment, and the quality of life is greatly affected.

In contrast, the targeting characteristics of antibody drug conjugates can minimize the damage to normal tissues, and reduce the side effects on humans while treating cancer. Therefore, antibody drug conjugates will have a broad future.

Established in 2004, Creative Biolabs is highly specialized in advanced antibody biochemistry and engineering. With more than a decade of exploration and expansion, our current research and service capacity covers the entire new drug discovery and development pipeline, ranging from early discovery, preclinical evaluations, cGMP manufacturing, to clinical trials. As a professional service provider in antibody-drug conjugates (ADCs) design and preparation, Creative Biolabs offers lysine conjugation strategy suitable for cost-effective and multi-scale preparation of various ADC products. We are committed to customarily design and conduct each project according to your budget, timeline, and specific requi

The Standards for Successful Antibody-drug Conjugates

What is an antibody drug conjugate? Antibody-drug conjugates (ADCs) bridged by smart linkers have an improved therapeutic window that efficiently targets tumor cells and tissues. ADCs comprise a high affinity antibody and a cytotoxic payload coupled by a suitable linker. The development of protein engineering, linker chemistry and new cytotoxic loads presupposes ADC to be a safe and effective anticancer therapy for personalized medicine. ADC has become a more powerful tool for targeting cancer treatment, and its "drug antibody ratio" (DAR) has also improved, and the number of clinical trials has also increased significantly.

Targeted antigen selection

Targeted antigens are the most important determinant, and their ideal characteristics are: 1 higher expression in tumors than in healthy tissues; such as Adcetris expression on mature and immature bone marrow cells is high in all AML patients. 2 The antigen is internalized by endocytosis in the presence of a ligand and circulated back to the plasma membrane. The internalization efficiency of an ADC depends on the choice of antibody, the epitope of the antigen, and the type of target. However, studies have shown that internalization of ADC is not necessary, such as SIP-F8-SS-DM1. 3 homogeneous antigen expression in the tumor microenvironment and low antigen abundance in circulation. 10,000 antigens per cell are the minimum number of antigens required. Furthermore, ADC antibody occasionally induces antigen-mediated anticancer activity. Other challenges for targeting tumor antigens with ADCs include high stromal tumor pressure, physiological and kinetic energy barriers, and bystander effects.

Antibody selection

Key points include antigen affinity, targeting specificity, good retention, minimal immunogenicity, low cross-reactivity, and circulation along the plasma. Most Abs currently used in humans are humanized or more suitable for humans. Most of the Abs in clinically tested ADCs are human immunoglobulin (Ig)-G isoforms, particularly IgG1, which can elicit more Ab-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) than other antibodies related tumor cell killing, such as trastuzumab in Kadcyla. In addition, bispecific antibodies can target both tumor cells and tumor-associated immune cells, but most of them are still in preclinical studies.

Linker selection

The linker is critical, which has a major impact on the therapeutic index, efficacy and pharmacokinetics of the ADC. It is characterized by: 1 stability, maintaining the Ab concentration in the circulation, preventing the drug from being released in advance, off-target, and the like. 2 Once in the cell, the linker is susceptible to cleavage and rapid release of the cytotoxic drug molecule carried. 3 good DAR value (drug-antibody ratio), can stably connect a large number of drug molecules, resulting in a homogeneous ADC. The current DAR value is targeted at close to 4. Cleavable linker: hydrazine, disulfide bonds and peptides. They correspond to low pH sensitivity, glutathione sensitivity and protease sensitivity, respectively. Peptide linkers are more stable than the other two, such as the cathepsin B-sensitive dipeptide bond (valine-citrulline) in Adcetris. In addition, although the PEG value of the pegylated β-glucuronide linker is higher, more research is needed. Non-cleavable linker: Contains non-cleavable thioether or maleimidocaproyl (mc), which relies on enzymatic degradation of the lysosomal internalization of the ADC to release a cytotoxic carrier, such as a thioether linker of Kadcyla.

ADC challenges and prospects

Extensive research is improving all components of the ADC. Immunohistology (IHC), circulating tumor cells, and imaging techniques have been used to evaluate viable biomarkers for determining patient populations. Protein scaffolds (divided into non-Ig scaffolds, Ab-derived scaffolds) have shown promise in the development of high-affinity ADCs. Given that the main obstacle to ADCs targeting solid tumors is tumor stroma, the recently focused tumor-matrix-targeted ADC is expected to open up new therapeutic windows for the treatment of solid tumors. We all look forward to more efficient antibody-drug conjugates to display their effects in the clinical treatment.

Established in 2004, Creative Biolabs is highly specialized in advanced antibody biochemistry and engineering. With more than a decade of exploration and expansion, our current research and service capacity covers the entire new drug discovery and development pipeline, ranging from early discovery, preclinical evaluations, cGMP manufacturing, to clinical trials. As an international cooperation, we have established offices all around the globe with more than 200 well-trained full-time scientists and technicians, who work closely with our customers and research partners to develop new medicines for a better, healthier world

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