ファージ、酵母、哺乳類などのディスプレイ法を用いた分子進化により、モノクローナル抗体や多重特異性抗体、抗体薬物複合体（ADC）、免疫療法、その他多くの構築物が生み出されました。コンピューターによるツールの出現は、効果的な薬剤候補への翻訳において、候補の選択、設計、有効性、成功の予測指標を改善するために応用されています。条件付き活性化アプローチにより、薬剤分子が活性化される前に腫瘍に到達できるようになり、標的外毒性や有害事象が軽減されます。抗体の機能活性を変化させるためのファージディスプレイの使用とともに、合成ライブラリーの開発やin vivo選択の戦略が探求されます。PEGS Europe Summitの基礎となる第10回年次会議「バイオ医薬品のディスプレイ」に参加し、新種の治療につながる進歩やアプローチについて耳を傾けてください。
William Harvey Research Institute, Queen Mary University of London
Molecular Immunology, Centre for Cancer Immunology, University of Southampton
Recommended Short Course*
Monday, 13 November, 14:00 - 17:00
SC1: Machine Learning Tools for Protein Engineering
*Separate registration required. See short courses page for details. All short courses take place in-person only.
Registration Open and Morning Coffee07:30
ADDRESSING DIFFICULT TARGETS WITH DISPLAY TECHNOLOGIES
KnotBodies: Creating Ion Channel Modulating Antibodies by Fusing Knottins into Antibody Loops
Venom derived cysteine-rich miniproteins (knottins) have potential as therapeutic agents to block ion channels but suffer from manufacturing difficulties, short half-lives and a lack of specificity. Maxion have developed a novel molecular format wherein the knottin replaces a peripheral CDR loop of an antibody. This format (termed KnotBodyTM), combines the best features of both molecular classes. The presentation illustrates the generation of KnotBody inhibitors of multiple ion channels and their optimisation using phage and mammalian display.
KEYNOTE PRESENTATION: Antibodies Binding to GPCRs in Different Conformations
G protein-coupled receptors are important drug targets for agonists and antagonists, depending on the application. We have carried out a massive selection of antibody Fab fragments against one GPCR using different strategies, and we have now been able to determine the structure of many different GPCR-Fab complexes at high resolution with cryo-EM. This wide range of different complexes allows unprecedented insight into receptor conformations and how to stabilize them.
A Library Approach for the de novo High-Throughput Isolation of Humanized VHH Domains with Favorable Developability Properties Following Camelid Immunization
We have generated a novel library approach for high-throughput de novo identification of humanized single-domain antibodies following camelid immunization. We demonstrate that by exploiting this approach, humanized high-affinity sdAbs with an optimized in silico developability profile can be generated that display favorable biophysical, biochemical, and functional attributes and do not require any further sequence optimization.
Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing10:30
CONDITIONALLY ACTIVATED BIOLOGICS
From Clustering Activated Agonists to SWITCH-DARPins
Immune cell-engaging and activating drugs show great value for patients, and have pathed the way for a next-generation of molecules optimized for depth and duration of response. For the most potent of these molecules, disease-restricted activation will be a key requirement to enable safe and efficacious dosing. Based on our DARPin (Designed Ankyrin Repeat Protein) modality, we have built various such design approaches. We will present an update on our tumor-activated FAPxCD40 program (MP0317), and introduce a novel SWITCH-DARPin approach, allowing disease-restricted activation based exclusively on the binding of tumor targets in the diseased area.
ALG.APV-527: Design of a Bispecific Tumor Antigen-Conditional 4-1BB x 5T4 Agonist that Mediates Strong T Cell Activation and Potent Anti-Tumor Activity
ALG.APV-527 was generated by incorporating binders obtained from the Alligator GOLD library into Aptevos ADAPTIR format, and was designed for 5T4-conditional 4-1BB-mediated anti-tumor activity. Preclinical in vitro and in vivo models demonstrate potential to minimize systemic immune activation and hepatotoxicity, while providing efficacious tumor-specific responses. ALG.APV-527 has potential as a promising anti-cancer therapeutic for the treatment of 5T4-expressing tumors and is currently evaluated in a Phase 1 study.
SELECTING DISPLAY TECHNOLOGY FOR DEVELOPABILITY
When Evolutionary Distance Matters: Generation of Mono- and Multi-Specific Humanized Antibodies by Chicken Immunization and Yeast Display Screening
We generated a platform for the discovery of antibodies by chicken immunization, followed by transfer of antibody diversity, to yeast for surface display screening (YSD). Antibodies with broad epitope coverage are obtained. Common light chain antibodies can be isolated for modular assembly of multi-specifics. CDR transplantation to a human framework with partial randomization of signature residues, followed by YSD screening of high-affinity variants, allows for straightforward humanization.
Mammalian Antibody Display: Microfluidic Hit Discovery and Their Fruitful Combination
Mammalian display libraries can be interrogated consecutively for manufacturability and specificity. Pre-enriched libraries secreting antibodies are a perfect match for microfluidics-assisted high-throughput screening. Options for (and recent advances in) combining these emerging technologies will be discussed.
New Large Explorer Modular semi-synthetic Phage Library with potential antibody diversity of 1.10E+27. Propriety Mammalian Display Technology to optimize antibodies and multi-specifics for optimized developability, Easy Transfer from Explorer to Mammalian Display & Expression to Optimize Ab Repertoires in Final Ab Format and deliver therapeutic lead candidates.
Assessment of off-target antibody reactivity is a regulatory requirement for clinical development. However, conventional screening methods are often ineffective in screening newer therapeutic modalities, including cell therapies. We will present the Membrane Proteome Array (MPA): a 6,000-protein cell-array for specificity screening, case studies describing its successful use for regulatory filings, and the status of the MPA being developed as a qualified Drug Development Tool under consideration by the FDA.
Refreshment Break in the Exhibit Hall with Poster Viewing16:10
Selecting Novel Antibody Leads against SLC Transporters Using the Linkster Discovery Platform
Antibody discovery against ion channels, GPCRs, and SLC transporters is very challenging. Failing drug campaigns, leading to non-developable antibodies, are often associated with display technology unfit for low target stability, and uncontrolled selection conditions. Here, case studies using the Linkster discovery platform demonstrate that developable and highly stable, conformation-specific antibody starting points can be reliably generated within 3 weeks, through smart library design (here in the form of optimised synthetic VHH libraries) and novel selection and screening technology.
NOVEL SELECTION STRATEGIES OF ANTIBODIES
Discovering Functional Modulators of the Ion Channel Kv1.3 from Engineered Peptide and Antibody Libraries
Synthetic antibody libraries were designed featuring ShK, a natural peptide that is a potent modulator of the ion channel Kv1.3, as the CDRH3 region of a cow VH domain. ShK sequence variants were engineered to enhance specificity for Kv1.3 over Kv1.1. Library hits were evaluated for activity and specificity in high-throughput e-phys studies, and compared to mAbs from naive and immunized cow antibody libraries, and from engineered chickens producing human sequence antibodies.
Selection and Validation of TCR-Like Antibodies and TCRs for Adoptive Therapy
CAR T cell products have entered mainstream therapy of leukemias. To further build on these real-world successes, and to expand adoptive therapy to solid tumors, there is a need for tumor-selective targets, as well as strategies to create or retrieve receptors that recognize such targets. In this presentation, the selection and validation of targets, and more specifically, corresponding receptors is highlighted- including TCR-like antibodies, as well as TCRs directed against cancer-selective peptide: MHCs. Besides the translational route, the introduction of such receptors in Phase I trials and their future outlook is discussed.
Welcome Reception in the Exhibit Hall with Poster Viewing18:30
Close of Display of Biologics Conference19:30
- Antibody-Based Therapies
- Emerging Targets & Approaches
- Membrane Protein Targets
- Safety & Efficacy of Bispecifics
- Advancing Bispecifics
- Engineering Bispecifics
- Optimisation & Developability
- Analytical Characterisation
- Protein Stability & Formulation