ADC Therapeutic Targets in Breast Cancer

 

Breast cancer is the leading cause of death among women worldwide. When breast cancer spreads to other parts of the body, the prognosis is poor. Currently, there is no treatment for metastatic breast cancer. Antibody-drug conjugates (ADCs) are new anti-cancer drugs composed of antibodies, ADC linkers and cytotoxic agents. 

Author: Carrier Taylor, Director of BOCSCI 

 

The monoclonal antibodies in the ADC target specific antigens, and the cytotoxic agent kills cancer cells without harming surrounding healthy cells. Ado-trastuzumab Emtansine (T-DM1), Fam-trastuzumab Deruxtecan (T-DXd) and Sacituzumab govitecan (SG) are FDA-approved ADCs for the treatment of breast cancer. T-DM1 and T-DXd target human epidermal growth factor receptor 2 (HER2), while SG targets trophoblast surface antigen 2 (TROP-2). Datopotamab deruxtecan (Dato-DXd) is an investigational ADC targeting TROP2. In the TROPION-Breast01 Phase III trial, the drug showed a clinically meaningful improvement in progression-free survival in breast cancer patients. Both TROP-2 and HER2 are involved in cancer cell proliferation. In addition to HER2 and TROP2, there are other proteins involved in tumor progression that could serve as important targets for ADCs.

Nectin Cell Adhesion Molecule 4 (Nectin-4)

Nectin-4 is a cell surface protein that plays an important role in cell-cell adhesion. It is overexpressed in breast cancer and other malignancies and promotes cancer cell proliferation and metastasis. Enfortumab vedotin (EV), a nectin-4-targeting ADC, has been approved by the FDA for the treatment of urothelial cancer. The drug has also been approved in the EU and China. The EV-202 Phase 2 trial is ongoing to test the efficacy of EVs in breast cancer and other nectin-4-expressing cancers.

 

Fig. 1. Structure of Nectin-4 (European Journal of Pharmacology. 2021, 911: 174516).

Tissue Factor (TF)

TF is a transmembrane protein mainly involved in blood coagulation. Scientists have discovered that this protein can promote cancer progression and metastasis. Tisotumab vedotin (TV), a TF-targeting ADC, has received accelerated approval from the FDA for the treatment of cervical cancer. However, this ADC has not yet been tested in breast cancer patients. XB002 is another ADC targeting TF. Scientists found in preclinical studies that the drug was effective against different types of tumors. XB002 caused reversible adverse reactions such as dry eye and non-infectious conjunctivitis in patients with solid tumors in phase I clinical trials.

Fig. 2. Mechanism of action of Tisotumab vedotin (Cancer Management and Research. 2023, 1063-1072).

Mesothelin

Mesothelin is another cell surface protein that plays an important role in cell adhesion. This cell surface protein is mainly expressed in mesothelial cells of the conjunctiva, pericardium, and cornea. It is also overexpressed in cancer and associated with poor prognosis. Anetumab ravtansine (AR) and RC88 are two ADCs that target mesothelin. In Phase I clinical trials, anetumab ravtansine caused manageable adverse effects, such as keratitis, fatigue, and anorexia, in patients with solid tumors. Both ADCs are being tested in phase 1/2 trials in triple-negative breast cancer and other solid tumors.

LIV-1

LIV-1 is a transmembrane protein that transports zinc into cells and is overexpressed in breast tumors. LIV-1 expression is associated with cancer metastasis and lymph node involvement. Ladiratuzumab vedotin (LV or SGN-LIV1A) is an ADC consisting of a monoclonal antibody targeting LIV1. This ADC can induce immunogenic cell death, which may be beneficial for patients undergoing immunotherapy. The drug’s efficacy is being tested in a Phase 1 clinical trial in patients with LIV1-positive breast cancer. Preliminary results from the clinical trial showed an overall response rate (ORR) of 32% in breast cancer patients. Median progression-free survival (PFS) was 11.3 weeks. This drug can cause nausea, hair loss, fatigue, and peripheral neuropathy in patients. Preliminary results from a phase Ib/II trial showed an ORR of 35% in triple-negative breast cancer patients treated with the combination of ladiratuzumab vedotin and pembrolizumab.

Fig. 3. Structure of ladiratuzumab vedotin (Expert opinion on investigational drugs. 2022, 31(6): 495-498).

Receptor Tyrosine Kinase-Like Orphan Receptors 1 and 2

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) plays an important role in nervous system development. It is overexpressed in triple-negative breast cancer and has shown antitumor activity against this breast cancer subtype in xenograft models. NBE-002 is an anti-ROR1 ADC being tested in patients with solid tumors in a Phase 1/2 clinical trial. Receptor tyrosine kinase-like orphan receptor 2 (ROR2) plays an important role in the development of the skeletal system. It also promotes breast cancer metastasis, leading to poor prognosis. Ozuriftamab vedotin (BA3021) is a conditionally active biological (CAB) ADC targeting ROR2 that is being tested in a Phase 1/2 clinical trial.

Fig. 4. Structure of ROR1 (Frontiers in Oncology. 2021, 11: 680834).

Human Epidermal Growth Factor Receptor 3 (HER3)

HER3 belongs to the human epidermal growth factor receptor (HER) family. The tyrosine kinase activity of HER3 is weak and cannot transduce signals. Therefore, it forms heterodimeric complexes with hepatocyte growth factor receptor (HGFR), fibroblast growth factor receptor 2 (FGFR2), and other receptor tyrosine kinases (RTKs). It is overexpressed in breast cancer and other cancers such as melanoma and head and neck cancer. Patritumab deruxtecan is an ADC targeting HER3 that has been tested in breast cancer patients in a Phase 1/2 clinical trial. The ORR for patients with HR-positive/HER3 high & low/HER2-negative breast cancer who received this drug was 30.1%. The drug also causes adverse effects such as decreased platelet and neutrophil counts and anemia.

Fig. 5. Mechanism of action of HER2- and HER3-targeting ADCs (Cancers. 2021, 13(5): 1047).

Globohexaosylceramide (Globo-H)

Globo-H is a carbohydrate antigen expressed in cancer cells. OBI-999 is an anti-Globo-H ADC that has been tested in patients with solid tumors in a Phase 1 clinical trial. Patients received the drug intravenously at varying doses and found the drug to be well tolerated at doses up to 1.2 mg/kg. The drug causes adverse reactions such as anemia and neutropenia.

Folate Receptor Alpha (FRα)

FRα is a membrane-bound protein involved in folate transport. It is expressed in triple-negative breast cancer. MORAb-202 is an ADC consisting of a monoclonal antibody targeting FRα. In xenograft mouse models, the drug inhibited proliferation of FRα-expressing cell lines. In a phase 1 clinical trial in which the drug was administered to patients with solid tumors, common adverse reactions observed in patients were neutropenia and leukopenia.

B7 Homolog 4 Protein (B7-H4)

B7-H4 is an immune checkpoint protein that inhibits the function of activated T cells. It is expressed in breast cancer and other tumors such as endometrial and cholangiocarcinomas. AZD8205 and SGN-B7H4V are two novel ADCs targeting FRα. Both ADCs showed antitumor activity in mouse models. A Phase 1/2 clinical trial is underway to evaluate the safety of AZD8205 in tumors such as breast cancer. SGN-B7H4V is also currently being tested in Phase 1 clinical trials in breast cancer and other tumors.

ADCs have been developed against these targets, and many of them have been found to be well tolerated in clinical trials. Scientists hope that some of these ADCs may be effective in treating metastatic breast cancer.

 

References

Kundu, C.N. et al. Nectin cell adhesion molecule-4 (NECTIN-4): A potential target for cancer therapy. European Journal of Pharmacology. 2021, 911: 174516.

Agostinelli, V. et al. Therapeutic Potential of Tisotumab Vedotin in the Treatment of Recurrent or Metastatic Cervical Cancer: A Short Report on the Emerging Data. Cancer Management and Research. 2023, 1063-1072.

Rizzo, A. et al. Ladiratuzumab vedotin for metastatic triple negative cancer: preliminary results, key challenges, and clinical potential. Expert opinion on investigational drugs. 2022, 31(6): 495-498.

Zhao, Y. et al. Tyrosine kinase ROR1 as a target for anti-cancer therapies. Frontiers in Oncology. 2021, 11: 680834.

Yonesaka, K. et al. HER2-/HER3-Targeting Antibody-Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR Inhibitors. Cancers. 2021, 13(5): 1047.

 

 

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The Process of Medical Device Creation When It Comes to 3D Printing, Modeling, and Engineering

 

3D Printing

 

Also called additive manufacturing (AM), 3D printing uses instructions from a digital file to create a 3-dimensional object one layer at a time. Each layer represents a “slice” of the finalized object. Anything that can be envisioned as thousands of thin layers that come together to create a solid object can be represented in a digital file that tells a 3D printer how to replicate that object.

 

Manufacturers of medical devices find that 3D printing is an efficient way to use the materials their devices are made from. Because each device can be printed on demand from a customized file, 3D printing allows device manufacturers to create devices based on the individual end user’s exact specifications. Rather than warehouses of identical parts that then have to be customized to the patient, a manufacturer only has to store the end user’s detailed measurements in digital form, then create one ready-to-use device specific to that user.

 

 

Dentures, eyeglasses, and titanium replacement hip joints are some examples of medical devices that can be 3D modeled and 3D printed. These medical devices can be customized not only to the patient’s individual anatomy, but also to their lifestyle choices. For example, a patient who plans to compete in athletic events may need a more lightweight device than another patient with a more sedentary lifestyle; different materials can be used to print their devices.

 

Porous metal foams used in some 3D printed medical devices that are meant to contact living bone tissue can be highly customized as to the size, distribution, and number of pores in the foam. This helps with the process of osseointegration, the bonding between the bone tissue and the device. Patients with these kind of porous metal foam devices statistically need fewer visits to emergency rooms than patients with more traditional prostheses.

 

3D Modeling

 

3D modeling (also spelled modelling) uses computer software to create a 3D model of an object that exists in the real world. It captures the object’s texture, size, and shape, converting them into coordinate data that appears within the program’s matrix structure. This data then becomes the digital file that can be used to create that object using 3D printing. Examples of this type of software include AutoCAD, Blender, TinkerCAD, ZBrush, and Autodesk Maya.

 

In health care, surgical teams sometimes take extensive measurements of images of a patient and use 3D modeling to plan exactly how they’re going to perform a surgical procedure in the specific patient’s body. Medical device manufacturers can use patient-specific 3D models of a patient’s bones to predict how a prosthetic device will fit the patient’s body. Health care providers typically take measurements and images directly from the patient’s body in person; in some cases, it may be possible to make highly detailed 3D models from a high-definition image. To create the highly precise images needed to 3D model parts of the human body, health care providers can use x-rays computed tomography (CT), magnetic resonance imaging (MRI), and other imaging technologies.

 

3D Engineering

 

Like 3D modeling, 3D engineering uses computer software to create a realistic, 3-dimensional image of an object. The difference is that while the object being modeling in 3D modeling exists in the real world, the digital object created by 3D engineering exists only in the software and in the engineer’s imagination. In other words, 3D engineering is used to design objects that have never existed before in the real world. Prototypes created by 3D engineering can quickly be created using 3D printing for a fraction of the cost of traditional manufacturing.

 

Written by Taylor McKnight, Author for GSC

 

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Three germ facts to shock you

 

Fact 1: 

There can be up to 10 million bacteria on your fingertips at any given time.

As your hands continue to touch other surfaces, new bacteria replace dead sources.

Fact 2:

A single gram of feces contains a trillion germs.

2 million bacteria per square inch are on the average public restroom floor.

Fact 3:

Flushing a toilet can spread droplets out of the toilet 3-6 feet.

Norovirus (stomach flu) can be easily spread in communal bathrooms as well as other non-obvious pathogens like SARS-CoV-2 (COVID-19).

 

Interesting facts, via Kismet Technologies. 

 

 

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Work in an MRI Lab? 6 Things You Can't Go Without

 

MRI labs are nests of marvels of modern technology. These labs ensure that individuals diagnosed with various medical conditions get the best imaging tests to guide their treatments. As an MRI lab technician, you know the importance of having all the right tools to conduct accurate, detailed, and timely testing. There are specific tools that MRIs just can’t go without, which is what this article will delve into. Continue reading to discover the top six tools that every MRI lab needs to do its job effectively.

 

By Dixie Somers

MRI Holding Coils

Any MRI lab needs to have a wide selection of holding coils that provide the compatibility and comfort required for MRI scan patients. These high-quality coils are specifically designed to coil around different parts of the body to ensure accurate scan results. They can be specifically-shaped for the region to help minimize discomfort during the scan process. It's essential to procure these coils as they are central to providing unparalleled imaging quality.

To ensure the longevity of these important tools, it's crucial to properly maintain them. This includes regular cleaning and proper storage after use. Holding coils should be wiped down with a disinfectant solution to prevent the spread of bacteria between patients. It's also important to check for any signs of wear and tear, such as fraying or cracks, and replace them if necessary. Proper storage in a cool, dry place can also help prevent damage and prolong their lifespan.

 

Contrast Agents

Contrast Agents are essential to enhance the clarity and the contrast of the images produced during the scans. These agents are primarily used for MRI perfusion imaging, and it's essential to have them at all times. Contrast agents are typically Gadolinium. Fortunately, Gadolinium contrast agents are relatively safe and can be used successfully in most patients. Having these contrast agents readily available will ensure that more detailed and accurate results are produced.

Proper handling and administration of gadolinium is crucial to ensure the safety and effectiveness of MRI scans. Before using any contrast agent, it's important to carefully read the product instructions and follow them precisely. This includes checking for any allergies or pre-existing conditions that may contraindicate the use of gadolinium.

 

Skilled Technicians

Having skilled and knowledgeable technicians is an essential factor for any MRI lab. These professionals are responsible for operating the machines, preparing patients for scans, and ensuring accurate image acquisition. With proper training and experience, they can also troubleshoot any technical issues that may arise during the scan process.

MRI lab technicians should have a solid understanding of MRI physics, anatomy, patient care, and safety protocols. They should also be able to communicate effectively with patients, doctors, and other medical staff. Regular training and education are crucial for technicians to stay up-to-date with advancements in MRI technology and procedures.

 

Medical-Grade Computers

Every MRI lab should be equipped with medical-grade computers that are safe, secure, and reliable. These computers are essential as they have the ideal software and hardware required for running DICOM viewers and Image reconstruction applications. Additionally, these computers should consistently produce detailed 3D images and run on a 64-bit operating system. Investing in modern, high-quality computers guarantees that operations can run seamlessly and stress-free.

To ensure that medical-grade computers are functioning properly, regular maintenance and troubleshooting should be conducted. This includes checking for any software updates or hardware issues that may affect the performance of the computer. It's important to have a designated IT specialist who is well-versed in medical-grade computer systems to troubleshoot any technical problems that may arise.

Additionally, it's crucial to have backup systems in place to prevent any interruptions in operations. Having multiple computers or a backup server can help mitigate any potential downtime and ensure that the MRI lab can continue functioning smoothly.

 

Quality Materials

MRI labs can't go without procuring high-quality materials. These may include wires, cables, and other essential accessories used in the MRI machine. These materials should be reliable and durable, so that they last a long time while functioning optimally. Procuring high-quality materials ensures accurate, quality results, and less breakages that can be hassling to fix.

To ensure that the MRI lab is well-stocked with quality materials, it's crucial to have a proper inventory system in place. This can include keeping track of the usage and expiration dates of materials, as well as regularly restocking them when necessary. It's also important to only purchase materials from reputable suppliers and to properly store them in a dry, temperature-controlled environment.

Conducting regular audits and reviews of the inventory can also help identify any materials that need to be replaced or restocked. By staying on top of materials management, the MRI lab can ensure that it always has high-quality materials available for use.  Overall, having a well-stocked inventory helps keep operations running smoothly and efficiently in an MRI lab.

 

Patient Comfort Tools

In addition to the essential tools and equipment mentioned above, it's also important for an MRI lab to have patient comfort tools. These may include items such as earplugs, blankets, an MRI Wheelchair, and headphones that can help make the scan experience more comfortable for patients.

Since MRI scans can be lengthy and somewhat intimidating for some patients, providing these comfort tools can help alleviate any anxiety or discomfort. Not only does this promote a more positive patient experience, but it also helps ensure that the images captured are of the highest quality as patients will be less likely to move or fidget during the scan.

As an MRI lab technician, you have a significant responsibility to ensure that the MRI lab is well-equipped to deliver accurate results. Procuring all the necessary tools mentioned above is central to running a well-functioning MRI lab. Ensuring that MRI labs have all these tools on hand will enable accurate diagnoses that restore people's health successfully.

 

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