June 25, 2022

Medical Trend

Medical News and Medical Resources

Drug Conjugates: Lung Cancer Antibodies to treat Personalized Tumor

Drug Conjugates: Lung Cancer Antibodies to treat Personalized Tumor

 

Drug Conjugates: Lung Cancer Antibodies to treat Personalized Tumor.  In recent years, nanotechnology and nanotherapy have had a profound impact on many fields of medicine. The biggest contribution of nanotherapy in cancer medicine is mainly derived from the development of new drug delivery systems, including liposomes, nanoparticles and more recently antibody-drug conjugates (ADC).

 


 1.    Introduction:

Antibody-drug conjugates are a new type of engineered anti-cancer drugs that consist of recombinant monoclonal antibodies (mab) covalently bound to cytotoxic compounds (defined as “payloads”) and target tumor-associated antigens. Their advantage is that they combine the high selectivity of monoclonal antibodies with the high titer (0.3-1 kDa) of cytotoxic drugs, and the IC50 value is in the sub-nanomolar range, thereby overcoming the limitations of traditional chemotherapy and targeted therapy.

The ADCs that have been approved by the regulatory authorities include Brentuximab Vidotin for CD30-positive Hodgkin’s lymphoma and Enmetrastuzumab for HER2-positive metastatic breast cancer. These two ADCs are used in The treatment of hematological malignancies and solid tumors has set a milestone, paving the way for multiple clinical trials evaluating more than 80 new ADCs in different tumors including lung cancer.

 

Lung cancer is the most common cause of death associated with cancer. In the past ten years, the treatment model of lung cancer patients has undergone fundamental changes. This is due to the identification of carcinogenic factors that can work, and the development of highly effective targeted therapy.

However, despite this progress, most patients with advanced lung cancer develop acquired resistance to targeted therapies, while other patients show intrinsic primary resistance to the treatment.

Antibody-drug conjugates preferentially target tumor cells expressing specific targets, providing a new therapeutic method for the treatment of advanced breast malignant tumors. This article discusses ADCs as the biological treatment of non-small cell lung cancer and small cell lung cancer. The scientific rationality, effectiveness and safety are reviewed.

 


 

2. The mechanism of action of antibody-drug conjugates

From the perspective of nanomedicine, ADC works as a self-targeting nanoscale carrier (Figure 1). These immunoconjugates overcome the limitations of traditional synthetic nanomedicines, such as lack of delivery to target cells, low cell internalization rate, and high clearance rate.

Antibody-drug conjugates exert their anti-cancer activity through different mechanisms, including induction of apoptosis, antibody-dependent cytotoxicity (ADCC), and/or complement-dependent cytotoxicity (CDCC) (Figure 2). After binding to the target antigen, the ADC is internalized in clathrin-coated endosomes. One of the mechanisms by which ADCs exert their anti-tumor effects is to induce cell apoptosis.

When the tumor-associated antigens are kinase receptors or other molecules that actively participate in signal transduction, this special mechanism occurs in the case of anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibodies.

The abnormal activation of HER2 promotes the proliferation of cancer cells by up-regulating gene expression. Some intracellular signaling pathways, such as phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) And RAS/RAF/extracellular signal-regulated kinase (ERK) can be effectively inhibited by ADC targeting HER2. In addition, preclinical evidence suggests that ADCs may exert anti-tumor activity through ADCC and CDCC.

Drug Conjugates: Lung Cancer Antibodies to treat Personalized Tumor

 

Drug Conjugates: Lung Cancer Antibodies to treat Personalized Tumor

 

 

 


 

3. Antibody drug conjugates in the treatment of non-small cell lung cancer

Non-small cell lung cancer is the most common malignant tumor of the chest, with the highest mortality rate among all cancers. The most common histological variants of NSCLC include adenocarcinoma (AC) and squamous cell carcinoma (SqCC). In recent years, molecular biology research on non-small cell lung cancer has allowed us to identify a subgroup of patients with specific gene mutations, including epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase (ALK) gene weight. row. If patients with non-small cell lung cancer have these operable genetic changes, they can be treated with tyrosine kinase inhibitors (TKIs), achieving unprecedented results in terms of survival. Similarly, other molecules that are overexpressed in non-small cell lung cancer cells can be targeted by some of the ADCs currently under investigation (Table 1).

Drug Conjugates: Lung Cancer Antibodies to treat Personalized Tumor


3.1 Antibody-drug conjugates targeting HER2

HER2 is a member of the receptor tyrosine kinase (RTK) EGFR family and is encoded by the erb-b2 receptor tyrosine kinase 2 (ERBB2) gene located in the chromosomal region 17q11.2-q12. After ligand-receptor binding, RTK may homodimerize or heterodimerize with other family members, thereby activating different downstream molecular pathways.

Heterodimers containing HER2 can mediate an effective oncogenic signal due to their high affinity and specificity for various ligands and their slow separation from growth factors. Although there is no approved HER2 targeted therapy in NSCLC, the biological relevance of HER2 as a carcinogenic driver of NSCLC has prompted the development of some targeted drugs, including two ADCs, namely (T-DM1) and (DS-8201a) .

 

3.1.1 Trastuzumab-Metansine Conjugate T-DM1

T-DM1 is the first ADC to enter the clinic since it was approved for the treatment of HER2-positive advanced or metastatic breast cancer. In the treatment of advanced breast cancer, safety is considered controllable. The most common adverse events of grade ≥3 included anemia (3.0%), thrombocytopenia (2.7%), and fatigue (2.5%). These adverse events are reversible after stopping the drug. In the preclinical model of NSCLC, T-DM1 shows significant pro-apoptosis and anti-proliferation effects, and is selective according to the expression level of HER2.

In a recent phase II trial, 18 patients with HER2 mutant lung ACs identified by next-generation sequencing (NGS) received the median of 2 previous systemic therapies, including HER2-directed therapy. T-DM1 treatment. The primary endpoint (ORR) reached a partial response of 44%, and the median duration of response (mDOR) was 4 months. All subtypes of HER2 mutations are responsive. mPFS is 5 months, mOS is 11 months. Toxic reactions included grade 1 or 2 infusion reactions, thrombocytopenia, and elevated serum liver enzymes, and only one case of grade 3 anemia. No patient needed to reduce the dose or stop treatment due to toxicity. In another cohort, 6 patients with HER2 amplification were included in the study. ORR was 50% (N=3), mPFS was 6 months, and mOS was 12 months.

In light of these results, the National Comprehensive Cancer Network Guidelines (NCCN) currently consider T-DM1 to be a treatment option for HER2 mutations, rather than HER2 overexpression NSCLC.

 

3.1.2 Trastuzumab deruxtecan (DS-8201a)

Trastuzumab deruxtecan (DS-8201a) is composed of a humanized anti-HER2 antibody, a topoisomerase I inhibitor payload, and a new type of linker. The drug-to-antibody ratio (DAR) is as high as 7-8. The pharmacological properties of DS-8201a have been evaluated in different HER2-positive cancer cells and various patient-derived xenograft (PDX) models. This ADC has shown good safety and effective anti-tumor activity in different tumor models (including tumor models resistant to T-DM1), regardless of the level of HER2 expression.

The bystander killing potential of DS-8201a was evaluated in in vitro and xenograft models. This ADC can kill HER2-positive cells and bystander HER2-negative cells without any effect on distant cells. The preliminary safety and activity data of DS-8201a in the first phase of HER2-positive NSCLC subjects are promising. Based on these preliminary data, compared with HER2 amplification (FISH assessment) and overexpression (IHC assessment) in patients with non-small cell lung cancer, HER2 mutation appears to be a more specific predictive biomarker of anti-HER2 treatment response. A phase II trial is currently underway to evaluate the efficacy of DS-8201a in advanced NSCLC patients with HER2 overexpression or HER2 mutations.

These patients have relapsed due to standard treatment or are ineffective or have no standard treatment [NCT03505710], which is expected to clarify DS- The potential status of 8201a in treatment.

 

3.2 Antibody-drug conjugates targeting Trop-2

Trophoblast cell surface antigen 2 is a transmembrane glycoprotein. It is encoded by the tumor-associated calcium signal transducer 2 (TACSTD2) gene located in the 1p32 region of chromosome, and is a new target for the treatment of solid tumors. It acts as a calcium signal sensor.

After binding to ligands such as insulin growth factor-1 (IGF-1), Trop-2 promotes the release of intracellular calcium and activates the ERK/mitogen-activated protein kinase (MAPK) pathway, thereby promoting cell survival. Unlike other oncogenes, the overexpression of Trop-2 has nothing to do with changes in gene structure, but is the result of dysregulation of the complex network of transcription factors, including inactivation of p63 and forkhead box protein p3 (FOXP3). Importantly, a recent meta-analysis of 16 studies (including 2 NSCLC cohorts) showed that tumor Trop-2 overexpression is associated with reduced survival and poor prognosis.

These data indicate that targeting Trop-2 plays a key role in lung cancer biology and may be a promising method for the treatment of NSCLC and small cell lung cancer (SCLC).

 

3.2.1 Sacituzumab govitecan (IMMU-132)

Sacituzumab-govitecan (IMMU-132) is an antibody-drug conjugate composed of humanized monoclonal antibody hRS7 and anti-cancer drug SN-38. SN-38 is the active metabolite of the anticancer drug irinotecan. By coupling SN-38 to a tumor-targeting antibody to deliver SN-38 to the tumor, it may be able to double the efficacy of the drug while reducing the system Sexual toxicity. In various animal models of human cancer, IMMU-132 significantly improves the survival rate and tumor regression.

There is no correlation between the efficacy of IMMU-132 and the expression level of Trop-2. Targeting Trop-2 is an attractive treatment strategy for solid tumors including lung cancer. However, identifying biomarkers that respond to IMMU-132 has always been a challenge, and patient selection still needs to be optimized.

 

3.3 Antibody-drug conjugates targeting c-MET

Mesenchymal epithelial transformation is an RTK encoded by the MET proto-oncogene, located in the 7q21-31 region of chromosome, and is closely related to tumor biology. It is expressed in a variety of normal tissues, and its ligand is hepatocyte growth factor (HGF). Ligand binding induces c-MET dimerization and activates MAPK, PI3K/AKT and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) downstream pathways, promoting cell survival, proliferation and invasion.

The overexpression of c-MET (IHC is defined as tumor cells with H score>150 or 2+/3+ staining intensity>50%) is associated with poorly differentiated histology and plays a key role in ADC selectivity. In view of the key role of MET in lung cancer biology, whether as a driver of primary cancer or as a driver of acquired drug resistance (such as EGFR-TKIs, ALK-TKIs), some MET inhibitors are under active research, including TKIs and ADCs. Here, we discuss two recently developed MET-directed adcs, namely telisotuzumab vedotin (ABBV-399) and SHR-A1403.

 

3.3.1 Telisotuzumab vedotin(ABBV-399)

Telisotuzumab vedotin (ABBV-399) is made of c-Met-targeting antibody ABT-700 coupled to toxin MMAE, and the two are connected by a valine-glutamic acid (VC) cleavable linker. The DAR value of ABBV-399 is 3.1, which can be seen as non-specific coupling. This ADC inhibits cell proliferation in NSCLC cell lines and induces tumor shrinkage in the c-MET overexpression PDX model.

Interestingly, ABBV-399 is active in tumor xenografts against ABT-700 (naked anti-c-MET monoclonal antibody). The Phase II trial of ABBV-399 in pretreatment of c-MET-positive NSCLC patients is currently underway [nct035339536]. In general, in clinical trials, this ADC failed to show convincing NSCLC activity, possibly due to improper patient selection. In fact, there is a lack of clinically reproducible biomarkers to guide ABBV-339.

However, ongoing clinical trials are expected to provide further evidence for the efficacy of ABBV-399 and will help us to better determine the role of ADC in the treatment of NSCLC.

 

3.3.2 SHR-A1403

SHR-A1403 is the second anti-c-MET ADC currently under clinical development. SHR-A1403 consists of a new cytotoxic microtubule inhibitor (SHR152852), which binds to the anti-c-MET humanized IgG2 monoclonal antibody through an irremovable linker, with a DAR of 2. In preclinical studies, SHR-A1403 showed an effective anti-tumor activity, which is related to the expression of c-MET. This ADC has also shown effectiveness in insensitive to anti-c-MET antibodies in a PDX model of hepatocellular carcinoma where c-MET is overexpressed.

This indicates that its anti-tumor effect is mainly mediated by cytotoxic payload, rather than inhibited by antibody-mediated signaling pathways. A phase I trial to study the safety and tolerability of SHR-A1403 in patients with advanced solid tumors is underway, including NSCLC that is ineffective to standard treatments, rather than selection based on c-MET expression [NCT03856541], and the results are waiting.

 

3.4 Antibody-drug conjugates targeting PTK7

Protein tyrosine kinase 7 (also known as colon cancer kinase-4, CCK4) is a catalytically inactive RTK-like protein, which was first discovered in colon cancer. It acts as a switch co-receptor in the canonical and non-canonical Wnt, semaphorin/plexin, and vascular endothelial growth factor receptor 1 (VEGFR1) pathways. These pathways are involved in cell communication and planar cells during embryogenesis and adult tissue homeostasis. Polarity and migration.

Depending on the receptor environment, the expression of PTK7 has been reported to be up-regulated in certain tumors, such as colorectal cancer, esophageal squamous cell carcinoma, and gastric cancer, or down-regulated in other tumors, such as renal cell carcinoma and melanoma. PTK7 was previously reported to be down-regulated in SqCC and AC, and was associated with a better prognosis of AC. Therefore, it has received more and more attention as a potential therapeutic target for non-small cell lung cancer. This article discusses the preliminary data of the new anti-PTK7 analog-to-digital converter PF-06647020.

 

3.4.1 PF-06647020 (PF-7020)

PF-06647020 (PF-7020) is composed of auristatin-0101, a microtubule inhibitor connected to the anti-PTK7 humanized monoclonal antibody through a cleavable linker. In preclinical PDX tumor models, PF-7020 induces stable tumor regression through a complex mechanism of action: reducing tumor-initiating cells with over-expression of PTK7, inhibiting angiogenesis and activating the immune system.

After 25 NSCLC patients were treated with PF-7020, regardless of the expression of PTK7, ORR was 16%, DCR was 56%, mDOR was 5.8 months, and mPFS was 2.9 months. It is worth noting that in this study, the activity of tumors with medium/high expression levels of PTK7 increased, indicating that there may be a linear correlation between PTK7 expression and the clinical efficacy of PF-06647020. However, these data are highly preliminary and worthy of further verification in clinical trials.

 

3.5 Antibody-drug conjugates targeting ALCAM/CD166

The activated leukocyte adhesion molecule (CD166) is encoded by the CD166 gene located in the 3q13.11 region of chromosome. It is a type 1 transmembrane glycoprotein that is expressed in neurons, fibroblasts, endothelial cells and keratinocytes. It mediates the adhesion between homophilic (CD166-CD166) and heterophilic (CD166-CD6) cells, and is involved in cell migration processes involving neuronal development, hematopoiesis, epithelial morphogenesis, and inflammation.

It can activate metalloproteinases and promote tumor proliferation, invasion and metastasis. Its overexpression is related to the poor prognosis of a wide range of solid tumors (including melanoma, mesothelioma, colorectal cancer, esophageal squamous cell carcinoma and endometrial cancer) [98102104-106]. The data on non-small cell lung cancer is contradictory. In fact, some studies have reported that CD166 expression is significantly associated with smaller tumor size and no lymph node metastasis, while other studies have reported that CD166 expression is significantly associated with shortened survival.

CX-2009 is a new type of anti-CD166-ADC, which is under clinical development for the treatment of solid tumors including NSCLC.

 

3.5.1 CX-2009

CX-2009 is a new type of ADC with a unique molecular structure. It is an “antibody-drug” based on the combination of anti-CD166 humanized monoclonal antibody and the effective microtubule maytansinoid payload (DM4). The Phase I/II trial of CX-2009 in patients with metastatic or locally advanced solid tumors is ongoing [NCT03149549], and the inclusion criteria include different tumor types expressing CD166 (such as breast cancer, prostate cancer, ovarian cancer, endometrial cancer, Head and neck cancer, cholangiocarcinoma and NSCLC). In this trial, patients were not selected based on CD166 expression, but an exploratory analysis was planned to assess the possible correlation between CD166 expression and CX-2009 activities. This study is expected to prove whether the innovative structure of this compound can provide high specificity and good safety clinically.

 

3.6 Antibody drug conjugates targeting NaPi2b

Type IIb sodium-dependent phosphate transporter is a multi-pass transmembrane protein responsible for the electrocotransportation of phosphate and sodium in epithelial cells. It is encoded by the solute carrier family 34 member 2 (SLC34A2) gene of chromosome region 4p15.2. An interesting therapeutic target in cancer. In lung tissue, NaPi2b participates in the synthesis of surfactants by alveolar type II cells. NaPi2b is highly expressed in NSCLC, papillary thyroid carcinoma and non-mucinous ovarian cancer. In NSCLC, the high expression level of NaPi2b has also been shown to be related to AC histology, the presence of EGFR mutations, and a better prognosis. NaPi2b targeted drugs, including ADC, are under clinical research on solid tumors.

 

3.6.1 XMT-1536

XMT-1536 is an ADC composed of the cytotoxic microtubule inhibitor payload MMAE, which is combined with a humanized anti-NaPi2b monoclonal antibody through a cleavable linker, and has a high DAR (12-15). After internalization, MMAE is converted by cathepsin into a highly active non-cell permeable metabolite, which limits its diffusion outside the target cell, thereby reducing the toxicity of the targeted system. The ADC has shown significant anti-tumor activity in preclinical studies.

The first human phase Ib trial of XMT-1536 in advanced solid tumors is currently underway [NCT03319628]. The inclusion criteria included cancer types that may express NaPi2B, such as NSCLC, ovarian cancer, and selected rare tumors (endometrial cancer, papillary renal cancer, papillary thyroid cancer, and salivary duct cancer). However, no selection was made based on the expression level of NaPi2b. The results of the dose-up phase showed that the doses of 20mg/m2 and 30mg/m2, administered every 3 weeks or every 4 weeks, were well tolerated. The 36 mg/m2 dose is still under evaluation.

Overall, this drug has shown a promising safety profile in several preclinical in vivo models. Whether XMT-1536 is also effective in clinical settings remains to be determined.

 

3.7 Antibody-drug conjugates targeting AXL

AXL is a member of the RTK family called TAM and is encoded by the AXL gene located in chromosome region 19q13.2. AXL is activated by growth inhibition specific protein 6 (GAS-6) or by gas 6 independent mechanisms, such as RTK (such as crosstalk between EGFR and MET). AXL is overexpressed in many tumor types such as lung cancer, breast cancer, thyroid cancer and ovarian cancer, and promotes the activation of PI3K/AKT/mTOR, MAPK/ERK and JAK/STAT signaling pathways.

In the NSCLC model, the down-regulation of AXL leads to an increase in the expression of E-cadherin, thereby increasing cell adhesion and inhibiting tumor cell migration. On the other hand, AXL overexpression promotes resistance to chemotherapy, targeted therapy and immunotherapy. The clinical relevance of targeted AXL in cancer proves that selective and multi-target AXL inhibitors, such as sunitinib and cabosantan IB, have been approved for the treatment of non-thoracic cancer, while other AXL inhibitors are under clinical research. Because AXL is highly expressed on lung cancer cell membranes, it is an attractive target for ADCs and is currently being developed and tested in early clinical trials.

 

3.7.1 Enalabutizumab (HuMax AXL ADC)

Enalabolismab vedotin (HuMax-AXL-ADC) is a new type of ADC, which is formed by combining a cleavable linker with a human IgG1 anti-AXL antibody. This ADC binds to cancer cells expressing AXL and releases MMAE, thereby inhibiting tubulin polymerization and leading to apoptosis. In the NSCLC-derived PDX model, enarbutizumab vedotin showed strong cytotoxic activity, including the PDX of AXL-expressing EGFR mutant TKI-resistant tumors. In view of the promising evidence of AXL targeted therapy for other solid tumors, the enabostimab-Vedotine trial from non-small cell lung cancer is eagerly anticipated.

 

 


 

4. Antibody drug conjugate

Treatment of small cell lung cancer Small cell lung cancer accounts for about 10-15% of all newly diagnosed lung cancers. It is characterized by a low survival rate and a 5-year mOS rate of 6%. It is worth noting that most patients with small cell lung cancer are diagnosed at an advanced stage of the disease, which makes them ineligible to receive curative treatments. In addition, although the initial objective response to first-line treatment (etoposide combined with platinum-based chemotherapy) is significant, small cell lung cancer is destined to make progress in a relatively short period of time.

Recently, on the basis of first-line treatment, the use of programmed death ligands 1 (PD-L1) inhibitor atezolizumab has made improvements in mPFS and mOS. However, the survival results achieved by the second-line treatment are quite disappointing. In addition to the addition of immunotherapy in the first-line treatment, the treatment model of advanced small cell lung cancer has not progressed much in the past 20 years.

Therefore, new second-line treatments represent related unmet clinical needs. Two different ADCs in SCLC are currently being studied: rovazumab ticillin (Rova-T) targeting delta-like protein 3 (DLL3) and saxituzumab-govetcon (IMMU) targeting Trop-2 -132) (Table 2). 

Drug Conjugates: Lung Cancer Antibodies to treat Personalized Tumor

 

4.1 Antibody-drug conjugates against DLL3

Delta-like protein 3 is a ligand that inhibits the NOTCH signaling pathway and is located in the cell membrane of normal cells. However, DLL3 may also be found on the surface of tumor cells, including SCLC cells that express DLL3 in 80% of cases. Although NOTCH activation is related to the occurrence of various malignant tumors, DLL3 seems to be a tumor suppressor. The mechanism of action and different expression levels between tumor cells and healthy cells make DLL3 a suitable target for ADC.

 

4.1.1 Rovalpituzumab tesirine(Rova-T)

Rova-T is an ADC for DLL3. In cell culture and xenograft models of high-grade neuroendocrine tumors, it shows promising anticancer activity. Recently, an independent data monitoring committee made a recommendation based on the observation that the mOS of the experimental group was shorter than topotecan, after which the registration work was interrupted. Although these results interrupted the development of Rova-T as a single agent for advanced small cell lung cancer, other trials are currently exploring the role of Rova-T as a maintenance treatment after first-line chemotherapy for advanced small cell lung cancer [NCT03033511]. In addition, Rova-T is being studied in conjunction with other anti-cancer drugs such as immune checkpoint inhibitors [NCT03026166].

 

4.1.2 Sacituzumab gavitecan (IMMU-132)

IMMU-132 is an antibody-drug conjugate composed of SN-38 (the active metabolite of irinotecan) and a humanized monoclonal antibody targeting trophoblast antigen-2 (Trop-2). Compared with etoposide, irinotecan has not achieved better efficacy in the first-line combination treatment of generalized small cell lung cancer, but preclinical data shows that compared with irinotecan alone, the combination of SN-38 and antibody May lead to a significantly improved therapeutic index.

 

 


 

5. Conclusions and future prospects

Antibody-drug conjugates are a kind of innovative anti-cancer drugs that can significantly improve the clinical efficacy of patients with solid malignancies and hematological malignancies. Although ADCs have not been approved for the treatment of NSCLC and SCLC, preclinical data and phase I/II clinical trials have shown encouraging results. However, there are still several issues to be resolved. First, the expression of ADC targets on the cell surface is theoretically a necessary condition for the activity of these drugs.

However, in the clinic, determining ADC targets for lung cancer has proven to be challenging. In fact, tumors are heterogeneous, and small samples, such as fine-needle aspiration biopsy or transbronchial biopsy, may not be representative of the entire tumor, which may lead to underestimation or overestimation of the existence of ADC targets. Second, a problem that needs to be properly addressed is whether higher target expression can predict a better response to a specific ADC in cancers that test positive for a specific target. However, clinical trials have shown that the response to ADC may also occur in cancers that lack surface expression of the target, which raises questions about the specificity of these drugs.

One limitation of ADC is its safety, because some clinical trials of ADC have shown unexpected DLT. Although this may seem surprising, because ADCs are expected to be selective for cancer cells expressing their target antigens, it is possible that part of the payload is lost in the bloodstream or eventually leaks from the target cells. On the other hand, the expression pattern of target antigens in healthy tissues is still unclear. Efforts are currently being made to reduce ADC-related toxicity. For example, in the design of CX-2009 and XMT-1536, interesting solutions were used to overcome the narrow therapeutic index usually associated with ADCs.

The antigen binding region of CX-2009 is masked by peptides that are preferentially cleaved by tumor microenvironment proteases, which limits the targeted toxicity to normal cells. The difference is that once the payload of XMT-1536 is released in tumor cells, it will be converted into a non-cell-permeable metabolite, thereby reducing the leakage of payload from target cells. In addition, antibody engineering techniques used to design bispecific antibodies (bsAbs) can develop more specific immunoconjugates. In fact, in bispecific ADCs (BSADC), one binding arm is designed to bind cancer cells, and the other binding arm is designed to promote the internalization and lysosomal release of the cytotoxic payload.

This strategy can improve the specificity and endocytosis of bsADCs, improve intracellular delivery, and reduce targeted toxicity and payload loss in the bloodstream. Another method currently being evaluated to increase the therapeutic index of ADC is to use a segmented dosing regimen, which may allow maintenance of dose intensity while reducing peak plasma concentrations. Another limitation of ADC is that, in most cases, acquired resistance will eventually occur. The molecular mechanism of resistance formation is unclear.

It is still unclear whether the drug resistance is caused by secondary mutations in genes encoding the target antigen and lysosomal pathway, or the target antigen itself may fall off the cell surface. In addition, it is still unknown whether epigenetic mechanisms can regulate the expression of ADC targets. This is a question that requires in-depth study.

 

In summary, ADCs are innovative and potentially powerful tools for the treatment of lung cancer. Some ADCs have been studied in early clinical trials and have achieved good results. More research work is currently underway to identify new target antigens and evaluate rationally designed ADCs and other anticancer drugs. New combination. In particular, some clinical trials are currently studying the combination of ADC and immune checkpoint inhibitors, based on preclinical evidence that ADC can enhance immune cell infiltration in tumors and trigger a strong anti-tumor response

 

 

(source:internet, reference only)


Disclaimer of medicaltrend.org