Greetings from the AACR Annual Meeting!
This year, we heard Joe Biden’s report on the progress of the Beau Biden Cancer Moonshot Initiative, compared immuno-oncology combination therapies, and mulled over the use of CRISPR screening to finding epigenetically controlled loci.
Joe Biden delivers the Cancer Moonshot Initiative update at AACR 2017
We also checked out the groundbreaking research being done by service providers on the Science Exchange network. Their work directly addresses the recommendations made last fall by the Moonshot’s Blue Ribbon Panel, and we are excited to give cancer researchers rapid access to these technologies through the Science Exchange platform!
Here are a few highlights from our exploration of #AACR17:
First humanized mouse model of tumor growth in bone: Pharmatest and Taconic Biosciences
The Moonshot Initiative’s recommendations specifically called out the potential of humanized mouse models to recapitulate the cellular architecture and heterogeneity found in human tumors. Traditional preclinical models that lack functional interactions between tumor, immune system and microenvironment have not been effective at predicting safety and efficacy of immunomodulating cancer drugs.
Taconic Biosciences showcases its novel animal models at AACR 2017
Pharmatest Services, Ltd. and Taconic Biosciences, both leaders in the development of predictive animal models, presented a poster at AACR 2017 showing the proliferation of human breast cancer cells in the bone injection site of humanized mice. The observed tumor growth, bone remodeling, and infiltration by human immune cells were similar to that seen in human breast cancer patients suffering from bone metastases.
Validation of this mouse model would be a very promising development for preclinical testing of immuno-oncology drug candidates and combination therapies.
Mass spectrometry imaging to characterize tumor microenvironment: Imabiotech
Imabiotech’s novel mass spectrometry imaging technology provides better toxicity and efficacy assessments in a number of therapeutic research areas, including immuno-oncology.
One challenge facing the Cancer Moonshot Initiative is that novel technologies are required to address tumor heterogeneity (at the cellular and molecular levels). Thus, the Blue Ribbon Panel called out multiplexed, quantitative imaging as a promising way to connect function with localization.
Imabiotech Corporation is a widely-published expert in the emerging field of mass spectrometry imaging, which is a promising technology to address tumor heterogeneity. Their poster and exhibit at AACR 2017 showcased how mass spectrometry imaging could be used to quantitatively characterize responses to immunotherapy in the tumor microenvironment, with spatial resolution.
Toward 3D patient-derived models of breast cancer, lung cancer, and glioblastoma: KIYATEC, Inc.
Another of the most challenging aspects of oncology is the fact that each patient has a different response to a particular therapy. Recognizing this, the Moonshot Initiative’s recommendations included a call to establish patient-derived test models, such as organoids and xenografts, in which candidate drugs could be tested before treatment.
KIYATEC presents 3D cell-based models for drug response profiling at AACR 2017
KIYATEC, whose expertise lies in generating and using 3D cell-based models for drug response profiling, presented their work on breast cancer, lung cancer, and glioblastoma multiforme (GBM), in three posters at AACR 2017.
One study addressed the challenges facing small cell lung cancer (SCLC) patients, for whom surgical resection is rarely feasible. Therefore, patient-derived tissue is difficult to obtain. KIYATEC was able to isolate functional cancer stem cells and circulating tumor cells, label-free, from SCLC patients, with the aim of developing 3D microtumors from these cells.
KIYATEC also showed that 3D models of breast cancer, which incorporated multiple stromal cell types and immune cells, responded differently to immune checkpoint inhibitors than standard 2D cell culture models. Finally, KIYATEC tackled GBM, for which therapy is particularly confounded by intra-tumor and inter-patient heterogeneity. They developed an efficient method to develop patient-derived 3D models, which may enable more personalized treatments for GBM.
Interested in working with these service providers? Order services on Science Exchange today, or contact us about your project.
Chemical structure of “emtansine” (mertansine plus linker) linked to a monoclonal antibody (maytansine black, mertansine modification red, linker blue.
The excitement around ADCs for treating cancer stems from the realization that traditional, small-molecule cytotoxic drugs and radiation are still some of the most potent anticancer agents, and that targeting them by tethering them to antibodies might bypass some of the side effects.
The recent founding investment by Johnson & Johnson of the ADC-focused startup, Fusion Pharmaceuticals, may provide some momentum to the development of targeted radiotherapeutics, a specific type of ADC. Johnson & Johnson’s investment followed on the heels of recent ADC investments by other large pharmas, including Boehringer Ingelheim and AstraZeneca. IMMU-132, the ADC being developed by Immunomedics, and SGN-LIV1A from Seattle Genetics are ADCs that are reported to target triple-negative breast cancer.
The biopharmaceutical industry currently has over two dozen ADC candidates estimated to be in its pipeline, indicating that there is a current demand for scientists with specific expertise in the techniques required for designing, synthesizing, and studying these molecules. In addition to developing expertise in-house, companies are frequently partnering with smaller companies or outsourcing projects to service providers to get the work done.
At Science Exchange, we have a unique bird’s-eye view of ADC-focused research and the service providers that are facilitating progress in this exciting field. Researchers who order services using the Science Exchange marketplace gain rapid access to an innovative network of 3,000+ service providers, including a number that supports ADC studies, through a single contract with Science Exchange. In this blog post, we’ll go through some of the key techniques and show how featured service providers in our network are meeting needs of ADC researchers.
Key techniques for studying ADCs: Science Exchange service providers step up.
Target discovery: the abundance challenge
Many ADC research programs seek to target cell surface proteins that are unique to the cell type that is to be killed by the cytotoxin. However, cell surface proteins, and other ADC targets, are usually low in abundance and underrepresented in traditional proteomic measurements.
One of the newest, cutting-edge providers on the Science Exchange network is Biognosys, offering discovery proteomics solutions based on Hyper Reaction Monitoring (HRM-MS™), a Next Generation proteomics technology. Invented at Biognosys, HRM-MS delivers quantification of up to 9’000 proteins per sample across treatments or conditions and identifies significantly regulated proteins. This platform is ideal for ADC target discovery studies, with one proof-of-concept study showing the quantification of over 500 cell surface proteins from matched biopsy samples.
The conjugation challenge
The ideal linker between the antibody and the cytotoxin drug is stable in the bloodstream, and if needed, can be cleaved in the specific environment of the target. Some ADC linkers are designed to dissolve the the reducing environment of the cytosol, while others require specific enzymes of certain subcellular compartments. Other linkers are non-cleavable. The linker also has to have minimal toxicity.
In addition to some wizardry in chemical synthesis, ADC development therefore requires experience in cell-based assays and drug metabolism studies. WuXi Apptec, MabPlex, and ChemPartner are service providers listed on the Science Exchange marketplace that have worked side by side with ADC developers on all aspects of linker synthesis and characterization.
Conjugation-related services that WuXi Apptec, ChemPartner and MabPlex provide include but are not limited to:
- Cytotoxin development
- Linker development
- Linker and cytotoxin conjugations
- Drug linking site determination
- Stability studies for ADC products
Bioanalysis in ADC development: the heterogeneity challenge
Unlike other categories of drug molecules, ADCs can be structurally heterogeneous, because of dynamic drug:antibody ratios (DAR) and variations in linker attachment chemistry. In a recent survey, 69% of researchers cited this structural heterogeneity as the #1 challenge facing bioanalysis in ADC development.
85% of the surveyed researchers reported using LC-MS for ADC bioanalysis. However, over 24% respondents had to adapt traditional LC-MS methods, using affinity capture LC-MS or accelerator MS. 42% of respondents reported using ligand-binding assays, illustrating that most researchers use more than one technique in analyzing ADCs. The complexity of analytes, in combination with the lack of regulatory guidance around ADC analysis, have resulted in the need to use multiple, individually developed, methods.
Fortunately, the Science Exchange marketplace features the services of Biognosys, Anaquant, and ChemPartner, all of which provide experience in developing analytical methods for ADCs.
To address the challenge of quantifying multiple species per sample, Biognosys provides targeted proteomics services using Multiple and Parallel Reaction Monitoring (MRM and PRM), which are techniques that offer highly specific and sensitive multiplexed quantification of selected proteins from complex biological samples. These techniques deliver absolute or relative quantification of up to 150 target proteins per run with a dynamic range of 6 orders of magnitude.
Countless other service providers, such as Bio-Synthesis, Bionova, and Maine Biotechnology Services, are experts in analyzing ADCs using ligand-binding assays. In addition, Science Exchange’s in-house regulatory compliance team has expertise in working with representatives from regulatory agencies, to ensure that the analytical services carried out by our service providers meet necessary requirements.
ADC bioanalysis services on the Science Exchange marketplace include:
- DAR (drug:antibody ratio) determination
- Residual free drug analysis
- Pharmacokinetics (PK) determination
Process development for ADC
Again, the heterogeneity of a batch of ADC can make it challenging to develop a scalable, reproducible, and robust manufacturing process. Manufacturing the antibody component of the ADC faces all the same challenges as does traditional therapeutic mAb production.
Given the demands of manufacturing, engineering quality by design is important in the nonclinical, preclinical and early clinical phases of ADC research. Expertise in antibody optimization, protein purification, and chemical synthesis are required to create less heterogeneous batches of antibodies, linkers, cytotoxins and conjugates.
Science Exchange service providers WuXi Apptec, MabPlex and ChemPartner all support ADC process development, with MabPlex’s services extending to GMP and scale-up (to kilogram scale).
Browse our marketplace for ADC-related services or contact our Concierge Service, who can match your project needs with the right service provider or a combination of service providers to move your ADC research forward.