Periodic Reporting for period 2 - SIMICA (Site-selective protein-modification chemistries for antibody-drug conjugates (ADCs))
Reporting period: 2021-01-01 to 2023-03-31
Cancer is the second leading cause of deaths all over the world only behind cardiovascular diseases. Nowadays cancer treatment is mainly achieved by small molecule cancer drugs (e.g. platinum-based agents). However, the success of this strategy is limited due to lack of selectivity for tumor cells. Targeted therapy is gaining importance due to its specificity towards cancer cells while sparing toxicity to healthy tissues. This approach targets specific receptors that are overexpressed on the surface of tumor cells. Monoclonal antibodies, peptides and hormones have been explored as biotherapeutics. As an innovative alternative, the therapeutic effect of these biomolecules can be further enhanced by their functionalization with toxic payloads (e.g. antibody drug‐conjugates, ADCs).
On the beginning, preparation of ADCs relied on insufficient site-selective conjugation strategies to attach drugs to antibodies, which yielded a heterogeneous mixture of antibodies with different drug loading at different sites. Indeed, it was soon found that this heterogeneity has a profound effect on the pharmacokinetics, efficacy and toxicity of an ADC. Currently, the most commonly used approach for the generation of antibody-conjugate therapeutics is the reaction of an engineered cysteine on the antibody’s surface with maleimides. A drawback is that maleimides may not be fully stable in blood resulting in a highly potent cytotoxic drug being released in healthy tissues.
It is commonly agreed that novel chemical methods for selective modification of proteins will enable the development of protein therapeutics with increased precision, improved linkage stabilities, and therapeutic efficiency. The main objectives of the SIMICA network are: 1) Place IMM within the core of the European Laboratories that seek to develop advanced methods to produce innovative biotherapeutics (e.g. ADCs); 2) Strength the science and technology capacity of IMM; 3) Improve training, mentoring and international exposure of IMM’s researchers; 4) Promote an entrepreneurial spirit in IMM’s community.
On the beginning, preparation of ADCs relied on insufficient site-selective conjugation strategies to attach drugs to antibodies, which yielded a heterogeneous mixture of antibodies with different drug loading at different sites. Indeed, it was soon found that this heterogeneity has a profound effect on the pharmacokinetics, efficacy and toxicity of an ADC. Currently, the most commonly used approach for the generation of antibody-conjugate therapeutics is the reaction of an engineered cysteine on the antibody’s surface with maleimides. A drawback is that maleimides may not be fully stable in blood resulting in a highly potent cytotoxic drug being released in healthy tissues.
It is commonly agreed that novel chemical methods for selective modification of proteins will enable the development of protein therapeutics with increased precision, improved linkage stabilities, and therapeutic efficiency. The main objectives of the SIMICA network are: 1) Place IMM within the core of the European Laboratories that seek to develop advanced methods to produce innovative biotherapeutics (e.g. ADCs); 2) Strength the science and technology capacity of IMM; 3) Improve training, mentoring and international exposure of IMM’s researchers; 4) Promote an entrepreneurial spirit in IMM’s community.
During the period covered by the report, SIMICA’s team has defined a long-term strategy in the scientific area of protein-drug conjugates. Several different goals have been accomplished. Efforts have been made to benefit from the techniques available across the consortium, and to stablish new collaborations, in order to gain access to other expertise that are not yet available within SIMICA. In particular, a IMM postdoctoral researcher has visit the University of Cambridge. Additionally, a collaborative work between IMM and Allcyte was stablished to evaluate the efficacy of a covalent binding BTK inhibitor using primary samples from patients with diffuse Large B-Cell Lymphoma (DLBCL). Under the course of the project a research contract has been also stablished between IMM and a US biopharma company (Neoleukin Therapeutics) to evaluate the efficacy of de novo therapeutic proteins against SARS-CoV-2 using animal models of disease currently implemented at IMM. Another important achievement was the prospect contact from IN-PART, a scouting company working with Johnson & Johnson for identification of potential academic partners working in the field of immunotherapies. On this regard, the SIMICA consortium worked together to submit a grant application for a call sponsored by J & J. Also of relevance, research groups at IMM have been contacted in order to promote future collaborations, aiming to improve the exploitation of the project and its results on the field of protein modification within IMM.
The consortium has also been responsible for regular communications on social media platforms and the project’s website, with the intention to maximize SIMICA’s impact, reaching not only the scientific community but the general public as well. Additionally, several training actions have been organized to improve the competences of IMM researchers in scientific writing and science communication. Lastly, in order to improve the researchers’ skills in the study area, the consortium has encouraged the participation in external conferences on the field.
The work previously developed enhanced the scientific capacity of IMM and increased the visibility of Portuguese research on the field of protein conjugation both nationally and internationally. For the next reporting period the consortium is preparing a summer school, a thematic workshop and interactive sessions with industry/enterprises to further promote innovation and entrepreneurship spirit within IMM. Similarly, staff exchanges, training actions and outreach activities will continue. Overall, the SIMICA consortium was able to mitigate the negative effects of the pandemic and successfully implement all the activities initially proposed.
The consortium has also been responsible for regular communications on social media platforms and the project’s website, with the intention to maximize SIMICA’s impact, reaching not only the scientific community but the general public as well. Additionally, several training actions have been organized to improve the competences of IMM researchers in scientific writing and science communication. Lastly, in order to improve the researchers’ skills in the study area, the consortium has encouraged the participation in external conferences on the field.
The work previously developed enhanced the scientific capacity of IMM and increased the visibility of Portuguese research on the field of protein conjugation both nationally and internationally. For the next reporting period the consortium is preparing a summer school, a thematic workshop and interactive sessions with industry/enterprises to further promote innovation and entrepreneurship spirit within IMM. Similarly, staff exchanges, training actions and outreach activities will continue. Overall, the SIMICA consortium was able to mitigate the negative effects of the pandemic and successfully implement all the activities initially proposed.
The implementation of the SIMICA project will promote the link between chemical biology and biomedicine in Portugal and will offer novel solutions for cancer targeted therapy with innovative biotherapeutics. The project increased the impact of the research output and will help sustaining a dynamic research in Portugal in the field of advanced methods for protein modification by expanding IMM activities to this research topic.
In terms of scientific progress, the consortium worked on the development of new chemical methods for labelling cysteine residues on proteins that is being applied to produce protein conjugates bearing toxic payloads or fluorophores for cancer therapy or imaging. Additionally, the team at the host institute has been applying such methods to modify proteins of interest with biophysical tags for imaging and pool down experiments that resulted in fruitful collaborations among different research groups at IMM. Of relevance, the team at IMM has taken advantage of specialized techniques available within the consortium, such us the innovative chemical methods to functionalize proteins available at the University of Cambridge, the Pharmacoscopy platform accessible through Allcyte for drug testing and the excellent imaging facilities existent at LUMC and Percuros.
On the other hand, the strengthening of networking will be used to prepare joint international research projects to attract competitive research funding to the host institute. The dynamic network interactions initiated during the project are indeed to be extended after its completion, further enhancing the project´s impact. Additionally, the social networks and outreach activities proposed will also provide a long-term impact for the Portuguese society by educating the general public how novel biotherapeutic approaches can advance cancer therapy. Lastly, the translation of the methods developed under timeframe of the project into economic and societal benefits will be at the horizon of SIMICA.
In terms of scientific progress, the consortium worked on the development of new chemical methods for labelling cysteine residues on proteins that is being applied to produce protein conjugates bearing toxic payloads or fluorophores for cancer therapy or imaging. Additionally, the team at the host institute has been applying such methods to modify proteins of interest with biophysical tags for imaging and pool down experiments that resulted in fruitful collaborations among different research groups at IMM. Of relevance, the team at IMM has taken advantage of specialized techniques available within the consortium, such us the innovative chemical methods to functionalize proteins available at the University of Cambridge, the Pharmacoscopy platform accessible through Allcyte for drug testing and the excellent imaging facilities existent at LUMC and Percuros.
On the other hand, the strengthening of networking will be used to prepare joint international research projects to attract competitive research funding to the host institute. The dynamic network interactions initiated during the project are indeed to be extended after its completion, further enhancing the project´s impact. Additionally, the social networks and outreach activities proposed will also provide a long-term impact for the Portuguese society by educating the general public how novel biotherapeutic approaches can advance cancer therapy. Lastly, the translation of the methods developed under timeframe of the project into economic and societal benefits will be at the horizon of SIMICA.