Executive summary
Across 50+ sessions and discussions the hottest topics in the antibody engineering and therapeutics industry in 2020 were explored.
From antibody discovery and developability, to advances in the latest technologies such as computational and machine learning, to, of course, engineering of COVID-19 antibodies.
Here University of Cambridge biochemist writer and entrepreneur Silvia Hnatova offers a summary of the key themes addressed in the keynotes.
Dr Janice M. Reichert, Executive Director of The Antibody Society, delivered the keynote presentation Antibodies to Watch in a Pandemic. The talk was divided into two parts: anti-SARS-CoV-2 antibodies being developed and the general trends for antibody approvals.
At the time of presenting (27 Aug 2020), two types of anti-SARS-CoV-2 antibodies have been granted regulatory approvals or are anticipated to gain approvals: repurposed antibodies and novel antibodies. Out of the existing antibodies, Dr Reichert identified common pathways being targeted: interleukin-6 or the receptor, GM-CF or the receptor, CS/a or the receptor. Most advanced antibodies are in Phase 2 or Phase 3 trials. Examples of antibodies authorized for therapy in COVID-19 patients are: levilimab (trade name Ilsira) registered for the treatment of patients with severe COVID-19 in Russia, itolizumab (trade name Alzumab) registered for the treatment of cytokine release syndrome in COVID-19 patients in India. Dr Reichert presented seven antibodies that are marketed for COVID-19 use in late-stage trials or in studies, that include the highly publicised remdesivir. She highlighted that the FDA can allow the use of 'unauthorized drugs for prevention, treatment of diagnosis of severe or life-threatening conditions, such as SARS-CoV-2'.
The highlight of the talk were anti-SARS-CoV-2 antibodies that are being tracked for use in COVID-19 patients. These represent ~100 small molecules, most of them mAb-based therapeutics. The most advanced anti-SARS-CoV-2 mAbs in Phase 2/3 trials include molecules developed by AbCellera and Eli Lilly and Company, and Regeneron. The completion dates for these antibodies are set in 2020/2021. Dr Reichert pointed out the strategy by Regeneron to roll several antibodies into clinical trials that have different ways of administration: one mAbs being administered intravenously and another subcutaneously. An intriguing part of the talk was focus on ostrich, cow and swine-derived anti-SARS-CoV-2 proteins. A recombinant ACE2, even though not antibody-based, was highlighted as a 'trap' protein that Dr Rechert is intrigued to compare to traditional mAbs in development. Overall, around '20 companies plan to progress anti-SARS-CoV-2 molecules into the clinic by the end of 2020', Dr Reichert said. She introduced an online tracker used for summarizing the latest developments in COVID-19 antibodies.
In the second part of the talk, Dr Reichert pointed out the increasing yearly trends of the number of antibodies gaining regulatory approval. The year 2020 will likely be ground-breaking in the number of antibodies obtaining regulatory approval, she highlighted. In addition to five already approved antibodies, at the end of July, there were eight other antibodies in review, three of which were expected to be improved by the end of August. She wrapped up the talk saying that 'projections into 2020 look good' and that she 'hopes that we have a record year in 2020 for the number of antibodies being approved'. Dr Reichert closed the keynote session by praising the global efforts for developing COVID-19 therapeutics.
Prof Dennis Burton from the Department of Immunology & Microbiology at Scripps Research Ragon Institute described his path towards the discovery of neutralizing antibodies (nAbs) to SARS-CoV-2, published by Rogers et al. (2020) in Science. His group recruited a cohort of COVID-19 patients to look at neutralizing and eventually monoclonal antibodies. The purpose was to set up neutralization assays to look at recombinant antibodies, isolate them and validate their activity in vivo in mice. For this, Prof Burton and his group developed neutralization assays for SARS-CoV-2. They obtained serum and PBMCs from mild to severe COVID-19 survivors near the symptom onset. They sorted around 2,018 IgGs from B cells from three donors. The majority of antibodies contained S spike, RBD and BG505 respectively. The binding of the antibodies, including the ACE2 binding, was confirmed via ELISA assays.
Prof Burton described the fascinating discovery of highly potent monoclonal antibodies against SARS-CoV-2. The antibody epitopes were binned to discover that most mAbs bind to RBD-A, RBD0B and S-A, respectively. The most potent mAbs are those directed against RBD-A, Dr Burton said, and they have very low levels of somatic hypermutation. Dr Burton described how he selected two neutralizing antibodies for validation in Syrian hamster model, in varying doses. Upon the administration of each of the two selected nAbs, hamsters are protected against COVID-19 showing significantly lower viral titers at higher antibody concentrations. Dr Burton pointed out that it is 'possible to generate escape variants' to account for potential resistance of the virus to the antibodies, by generating a cocktail of antibodies. Dr Burton concluded that 'RBD-A ACE2 binding site should be of major focus' for the development of neutralizing antibodies and COVID-19 vaccines.
Multiple intriguing talks touched upon the latest developments in cancer immunotherapies.
Prof Jeanette Leusen, Head of Immunotherapy group at University Medical Center Utrecht and Founder and CSO of TigaTx that engineers IgA as cancer therapeutics, delivered a fascinating keynote lecture on the role of neutrophils in the fight against cancer. She explained that myeloid derived suppressor cells (PMN-MDSCs) are the main obstacle to immunotherapy. PMN-MDSCs are indicators of poor prognosis because of their ability to suppress CD4 and CD8 T cells and induce suppressor macrophages. Prof Leusen aims to redesign PMN-MDSCs to activate appropriate cells, instead of suppressing them. She demonstrated her fascinating results leveraging IgA for inducing killing of cancer cells in in vitro assays. Prof Leusen explained that IgA, 'the most produced antibody in our immune system', induces activation of neutrophils via FcR activation. The question was, according to Prof Leusen, 'whether it would work in vivo'. Her group injected IgA1 into mice that resulted in decreased tumour volume in A431 lung metastasis SCID model. She explained the choice of IgA2 as opposed to IgA1 for therapeutic applications, as IgA2 had no association with Berger's disease.
Prof Leusen pointed out at the main challenge of therapeutic applications of IgA: short half-life. In addition to the half-life that is 'around 15 hours' for IgA in mice, she highlighted several other challenges for clinical use of IgAs and her strategies for overcoming them: the presence of a receptor and manufacturing issues, among others. Prof Leusen engineered several IgA molecules to resolve the challenges, leading to the successful IgA3.0 molecule that solves manufacturing, production and stability issues. The strategy used to increase the half-life of the protein was to attach an albumin domain to the molecule. IgA3.0 was demonstrated to work efficiently in vivo in mice, reducing tumour progression. Prof Leusen concluded her talk with the clinical potential for IgA3.0, that could be used for the atreatment of neuroblastoma. She said that IgA3.0 could be an 'alternative to dinutuximab that is FDA-approved but has a very severe side effect (neuropathic pain)', because of diminished binding to neuronal receptors. This was validated in vivo in mice: IgA bound to neurons but did not activate nociceptors, and successfully reached the tumour in mice.
Prof Sergio Quezada from the UCL Cancer Institute discussed his progress in the research of anti CTLA-4 antibodies. His research showed that reengineered anti CD25 antibodies deplete Tregs, in contrast to previous research that showed that anti CD25 antibodies fail to boost the activity of immunotherapies. In combination with anti PD-1, anti CD25 antibodies contributed to the rejection of established tumours, in eleven out of fourteen mice models.
Prof Quezada described his path towards developing clinical-grade anti CD25 antibodies. The strategy was to deplete Tregs without blocking IL2 receptors, to enhance the immune response. Prof Quezada developed such anti CD25 antibody, that after a single dose administration achieved a complete response in mice. This led to the development of the first human anti CD25 with non-interleukin blocking activity (CD25NIB, RG6292) that was acquired by Roche. RG6292 preferentially depleted Tregs in PBMCs in human tumour samples, including lung cancer and colorectal carcinoma, and activated effector T cells in humanized mouse models. Prof Quezada concluded the talk by highlighting that RG6292 is now in Phase I of clinical trials conducted by Roche, awaiting efficacy results.
Prof Hedda Wardemann, Head of Division of B Cell Immunology at the German Cancer Research Center, delivered a fascinating talk about how we can leverage our understanding of B cells to induce a potent B cell response via vaccination. Prof Wardemann focuses on the B cell response to Plasmodium falciparum. She highlighted that there is only one vaccine that succeeded in Phase III trials: the pre-erythrocytic RTS,S vaccine that is being trailed in African countries. Because the efficacy is only 50%, the hope is that improved design will improve efficacy, she said. The RTS,S vaccine targets the circumsporozoite protein (CSP) and Prof Wardemann specializes in the human anti-PfCSP antibody response. Her group generated a library of anti-CSP B cell antibodies and compared their strength. Some of them showed good immunization response, with the most potent antibodies being low-mutated or unmutated antibodies that accumulated in the host after multiple parasite exposures.
Most of the CSP antibodies were encoded by a specific gene combination and encoded antibodies with short motifs. 'These antibodies were detected in three out of the eight donors we observed', Prof Wardemann highlighted. She pointed out at the VH3-33 gene segment being the most prominent among the anti CSP antibodies. Because the motif encodes tryptophan, Prof Wardemann hypothesised that this motif may facilitate binding against CSP. She tested this by mutating the tryptophan residue to arginine or lysine, strongly reducing the binding strength to CSP.
The Human B Cell Response to a Repetitive Malaria Parasite Protein - Hedda Wardemann, Professor and Head, Division of B Cell Immunology - German Cancer Research Center
Prof Wardemann highlighted that for clinical use of anti CSP antibodies, we need to consider parasite's inhibitory activity of the antibodies. She closed the talk summarising that all potent CSP antibodies target the central repeat including the junction of the protein, that epitope cross-reactivity is associated with high affinity and that most potent PfCSP antibodies recognize a conserved epitope. She suggests that to develop CSP vaccine, 'the quality of anti-repeat response can be improved by promoting germinal center reactions and affinity maturation'.
Prof Serge Muyldermans from the Vrije Universiteit Brussel discussed nanobodies and their clinical applications. Thanks to harbouring camel blood, Vrije Universiteit Brussel was able to conduct strong research using camel antibodies, leading to several spinoffs working on nanobodies.
Prof Muyldermans told an interesting story about how blood from healthy and trypanosoma-infected camels was shipped to the university, establishing the research on IgG antibodies in dromedary. Efforts focused on cloning specific domains of the IgG antibodies could produce smaller antibodies, via library generation and nanobody selection. Prof Muyldermans then present several use cases of nanobodies and finally, target applications. Nanobody-facilitated tumour radiolysis and CAR-T cell therapy belong among the candidates for nanobody applications, using their small size, high affinity and specificity.
Prof Jannie Borst, Head of Department of Immunohematology and Blood Transfusion at the Leiden University Medical School introduced the cytotoxic T cells as potential means of targeting cancer immunotherapy during her Keynote Presentation on TNF Receptor Targeting. She is interested in stimulating T cell response via checkpoint inhibitors, to promote a cytotoxic response in cancer. She highlighted PD-1 as a target for promoting T cell response: PD-1 can inhibit both TCR and CD28 signalling.
She studied TNF receptors in mice and concluded that different receptors and ligands act sequentially to promote CTL survival in lymphoid and non-lymphoid tissues. She argued that a combination of CD27 agonism and PD-1 blockade is the most prospective cancer therapy, that her group is exploring in clinical trials as a multimodal cancer treatment.
TNF Receptor Targeting in Cancer Immunotherapy - Jannie Borst, PhD Head, Department of Immunohematology and Blood Transfusion - Leiden University Medical School
