Engineering Bispecific Antibodies Improving Therapeutic Properties for Oncology and Beyond  May 7-8 2020 • Boston, MA |  The universe of bispecific antibody platforms, combinations, strategies and chemistry is growing exponentially and the application of bispecific constructs in immunotherapy is proving to be an extremely effective combination. Fine tuning specificity, calibrating potency while minimizing safety risk are all top priorities of antibody engineers for targets in oncology, immuno-oncology and infectious disease. Early results with new platforms and evolving techniques will be shared.    https://www.pegsummit.com/Bispecific-Antibodies/

Bispecific Antibody Pipeline Congress  August 24-27, 2020 Washington DC  key opinion leaders including regulators, clinicians, and industry experts to deepen our understanding of bispecific therapeutics and exchange innovative ideas to foster meaningful research collaborations. https://www.bispecificantibodycongress.com/

Bispecific Antibody Therapeutics January 23-24, 2020, San Diego explores the challenges of engineering multi-specificity to achieve more effective therapies that bind to at least two molecular targets simultaneously. These next-generation antibody formats are showing efficacy in the efforts to conquer cancer and other diseases. Case studies will highlight novel engineering approaches that address safety, stability, enhanced targeting, and manufacturability. https://www.chi-peptalk.com/bispecific-antibody-therapeutics/

Bispecific engineering 2019 Nov 21-22 Lisbon Portugal therapeutics that have optimal stability and half-life, and proven functionality. Balancing the affinity of the two arms of the bispecific, especially for CD3 targeting products, is seen as a common challenge and efforts are clearly underway to overcome this for enhanced targeting and minimal toxicity.  https://www.pegsummiteurope.com/engineering-bispecifics/

Bispecifics & combination therapy: Advancing Bispecifics and Combination Therapy to the Clinic 2019 Nov 21-22 Lisbon Portugal features case studies for haematological and solid tumours, bispecific-like products and biotherapeutics in combination. Presenters explain the rationale for the choice of combination, the background to the mode of action and how the products perform, as well as PK profile, PK/PD relationships, safety/toxicology studies, getting the right potency: side effect balance, translational studies, and risk assessment. Where appropriate, investigators present clinical trial design, demonstration of safety, issues that have arisen and have been resolved, proof of concept, dose escalation studies, and interaction with clinicians. https://www.pegsummiteurope.com/advancing-bispecifics

CAR T, TIL and TCT therapy 2019 Nov 20-21 Lisbon Portugal The stunning success of CAR T therapy over the past couple of years has spawned a new industry and a proliferation of CAR, TCR and TIL constructs. Engineering efforts are aimed at improving the design, targeting, developability, manufacturing, and scalability of new formats to solve issues that remain, including improving the safety of immunotherapy, affordability and targeting of solid tumors. The tumor microenvironment and the microbiome are being tapped to predict the efficacy of immunotherapy and optimize results.  https://www.pegsummiteurope.com/CART-TILs-TCR

CAR Ts, TCRs and TILs Latest Innovations and Developments in Adoptive Cell Therapy May 6-7 2020 Boston MA  CAR Ts, TCRs and TILs focuses on the latest tools, techniques, and engineering strategies driving the development of cellular immunotherapies for cancer and immune disorders. Focus will be given to clinical progress with Chimeric Antigen Receptors (CAR), T Cell Receptors (TCR), Tumor Infiltrating Lymphocytes (TIL) and Natural Killer (NK) cells, with dedicated sessions on off-the-shelf platforms, solid tumors and lessons learnt from the clinic. https://www.pegsummit.com/TCellTherapy/

See also Chimeric Antigen Receptors CARs

cell based therapies: Cell therapy represents the most recent phase of the biotechnology revolution in medicine. As with many remedies, cell therapies are based on ground-breaking scientific discoveries and technology advancements. Most cell-based therapies are currently experimental, with a few exceptions such as haematopoietic stem cell (HSC) transplantation which is already a well-established treatment for blood related disorders [1,2]. The next generation of cell therapies now emerging are of diverse class. Cell therapies can be classified by the therapeutic indication they aim to address, e.g. neurological, cardiovascular, ophthalmological; by whether they comprise cells taken from and administered to the same individual (autologous) or derived from a donor (allogeneic); or most commonly by the cell types, often using the EU regulatory classification. The EU regulatory classification of cell-based therapies discriminates between minimally manipulated cells for homologous use (transplants or transfusions) and those regulated as medicines which are required to demonstrate quality, safety and efficacy standards to obtain a marketing authorization before becoming commercially available (referred to as Advanced Therapy Medicinal Products; ATMPs) which are further subdivided into somatic cell, gene therapy and tissue engineered products. Another way of considering the diversity of cell therapies is classification by their underlying technology. Broadly, the ATMP subdivisions are mirrored in the cell-therapy technology classification described in this paper. The technology, i.e. methodology, being used, rather than the specific cell type is often the feature that needs to be addressed to solve manufacturing, regulatory and clinical issues in a more general way. Thus, a technology classification can emphasize the commonality in translation challenges between otherwise diverse types of cell-based therapy. Mount NM, Ward SJ, Kefalas P, Hyllner J. Cell-based therapy technology classifications and translational challenges. Philos Trans R Soc Lond B Biol Sci. 2015;370(1680):20150017.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634004/

Chimeric antigen receptors (CARs, also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors) are engineered receptors that combine a new specificity with an immune cell to target cancer cells. Typically, these receptors graft the specificity of a monoclonal antibody onto a T cell. The receptors are called chimeric because they are fused of parts from different sources. CAR-T cell therapy refers to a treatment that uses such transformed cells for cancer therapy. Wikipedia accessed 2018 Aug 22 https://en.wikipedia.org/wiki/Chimeric_antigen_receptor

cellular therapy:  Cellular therapy products include cellular immunotherapies, cancer vaccines, and other types of both autologous and allogeneic cells for certain therapeutic indications, including hematopoetic stem cells and adult and embryonic stem cells.  FDA, Cellular & Gene Therapy products https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/  
Related terms: gene therapy, myoblasts, stem cells; Cancer  cancer vaccines See also high content analysis  Stem cells

Chimeric Antigen Receptors (CAR): Recombinant receptors that provide both antigen-binding and T-cell-activating functions. A multitude of CARs has been reported over the past decade, targeting an array of cell surface tumor antigens. … CARs are a new class of drugs with great potential for cancer immunotherapy. Upon their expression in T lymphocytes, CARs direct potent, targeted immune responses that have recently shown encouraging clinical outcomes in a subset of patients with B-cell malignancies. The basic principles of chimeric antigen receptor design. Sadelain M, Brentiens R, Riviere I, Cancer Discov. 2013 Apr; 3 (4): 388-398. doi: 10.1158/2159-8290.CD-12-0548. Epub 2013 Apr 2. http://www.ncbi.nlm.nih.gov/pubmed/23550147

Receptors, Chimeric Antigen: Synthetic cellular receptors that reprogram T-LYMPHOCYTES to selectively bind antigens. MeSH 2019

combination products: Regulatory

developability biologics: Monoclonal antibodies constitute a robust class of therapeutic proteins. Their stability, resistance to stress conditions and high solubility have allowed the successful development and commercialization of over 40 antibody-based drugs. Although mAbs enjoy a relatively high probability of success compared with other therapeutic proteins, examples of projects that are suspended due to the instability of the molecule are not uncommon. Developability assessment studies have therefore been devised to identify early during process development problems associated with stability, solubility that is insufficient to meet expected dosing or sensitivity to stress. This set of experiments includes short-term stability studies at 2-8 þC, 25 þC and 40 þC, freeze-thaw studies, limited forced degradation studies and determination of the viscosity of high concentration samples.  Yang X, Xu W, Dukleska S, et al. Developability studies before initiation of process development: Improving manufacturability of monoclonal antibodies. mAbs. 2013;5(5):787-794. doi:10.4161/mabs.25269. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3851230/  See also Drug discovery & Development developability

DNA vaccines: Recombinant DNA vectors encoding antigens administered for the prevention or treatment of disease. The host cells take up the DNA, express the antigen, and present it to the immune system in a manner similar to that which would occur during natural infection. This induces humoral and cellular immune responses against the encoded antigens. The vector is called naked DNA  because there is no need for complex formulations or delivery agents; the plasmid is injected in saline or other buffers. MeSH, 1997    Broader term: vaccines 
Wikipedia https://en.wikipedia.org/wiki/DNA_vaccination 

domain antibodies:  The smallest known antigen- binding fragments of antibodies, ranging from 11 kDa to 15 kDa. ... owing to their small size and inherent stability, can be formatted into larger molecules to create drugs with prolonged serum half- lives or other pharmacological activities. LJ Holt et. al, Domain Antibodies: Proteins for Therapy, Trends in Biotechnology, 21 (11): 484- 490, Nov. 2003

formulation biologics: Drug delivery

fusion protein therapeutics: Engineering for Clinical Success APRIL 8-9, 2019 Boston MA  Chimeric fusion proteins, with their ability to extend plasma half-life and prolong therapeutic activity, offer exciting benefits over antibody-based therapeutics. Companies are intensely investigating into fusion protein therapeutics as a promising alternative to antibodies. https://www.pegsummit.com/protein-therapeutics/ See also recombinant proteins

The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. MeSH, 1989

Gene Therapy covers both the research and clinical applications of the new genetic therapy techniques currently being developed. Over the last decade, gene therapy protocols have entered clinical trials in increasing numbers and as they cover a wide spectrum of diseases, these studies promise to unite the diverse organ-based specialties into which modern medicine has become divided. Gene Therapy covers all aspects of gene therapy as applied to human disease, including: novel technological developments for gene transfer, control and silencing, basic science studies of mechanisms of gene transfer and control of expression, preclinical animal model systems and validation studies, clinical trial reports which have significant impact for the field, gene-based vaccine development and applications, cell-based therapies including all aspects of stem cells and genetically modified cellular approaches. Aims and Scope, Gene Therapy, Nature https://www.nature.com/gt/about

The term 'gene therapy' encompasses at least four types of application of genetic engineering for the insertion of genes into humans. The scientific requirements and the ethical issues associated with each type are discussed. Somatic cell gene therapy is technically the simplest and ethically the least controversial. The first clinical trials will probably be undertaken within the next year [1986]. Germ line gene therapy will require major advances in our present knowledge and it raises ethical issues that are now being debated. In order to provide guidelines for determining when germ line gene therapy would be ethical, the author presents three criteria which should be satisfied prior to the time that a clinical protocol is attempted in humans. Enhancement genetic engineering presents significant, and troubling, ethical concerns. Except where this type of therapy can be justified on the grounds of preventive medicine, enhancement engineering should not be performed. The fourth type, eugenic genetic engineering, is impossible at present and will probably remain so for the foreseeable future, despite the widespread media attention it has received. W. French Anderson "Human gene therapy: scientific and ethical considerations" J Med Philosophy 10 (3): 275- 291, Aug. 1985  

Cellular & gene therapy, FDA, US http://www.fda.gov/cber/gene.htm 
Related terms: human gene transfer, genetic enhancement; DNA glossary: recombinant DNA  Molecular diagnostics: especially preimplantation diagnosis

genetic immunization: The concept and demonstration of genetic immunization (GI) was first introduced in 1992. At the time it appeared to be a revolutionary new approach in vaccinology. Since then, genetic immunization has been applied with much success in a wide variety of model and natural systems. It has also been used in several human clinical trials. Currently there is a general impression that genetic immunization has limitations inhibiting its broad use. The technique is thought to be poor at antibody production and more importantly not to work well in primates and humans (simian barrier). However, recent reports addressing these issues (poor antibody production and the simian barrier) showed improvements of GI to produce protective immune responses in humans. We propose that the apparent limitations of gene vaccines may arise from not using the technologies' potential to manipulate the immune system. This dearth of imaginative use is manifested in the tendency by some to term the technique DNA immunization. The apparent limitations of DNA vaccines may not be limitations for gene vaccines. Genetic Immunization Johnston, Stephen Albert et al Archives of Medical Research , Volume 33 , Issue 4 , 325 – 329  https://www.ncbi.nlm.nih.gov/pubmed/12234521  Related terms: DNA vaccines,  gene therapy

humanized antibodies; antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans.[1][2] The process of "humanization" is usually applied to monoclonal antibodies developed for administration to humans (for example, antibodies developed as anti-cancer drugs). Humanization can be necessary when the process of developing a specific antibody involves generation in a non-human immune system (such as that in mice). The protein sequences of antibodies produced in this way are partially distinct from homologous antibodies occurring naturally in humans, and  are therefore potentially  immunogenicwhen administered to human patients  … Humanized antibodies are distinct from chimeric antibodies. The latter also have their protein sequences made more similar to human antibodies, but carry a larger stretch of non-human protein.. Wikipedia accessed 2018 Nov 18 https://en.wikipedia.org/wiki/Humanized_antibody

immunocytokines: antibody-cytokine fusion proteins, with the potential to preferentially localize on tumor lesions and to activate anticancer immunity at the site of disease. Various tumor targets (e.g., cell membrane antigens and extracellular matrix components) and antibody formats (e.g., intact IgG and antibody fragments) have been considered for immunocytokine development and some products have advanced to clinical trials.  Neri D, Sondel PM. Immunocytokines for cancer treatment: past, present and future. Curr Opin Immunol. 2016;40:96-102.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215124/

immunotechnology:  Technology based on applications of cells and molecules of the immune system. A major research interest is the application of human recombinant antibodies and antibody fragments in medical and industrial applications, as well as studies of mechanisms underlying somatic mutations in B cells and IgE switch in allergy. The use of synthetic antibodies in proteome analysis, including protein array technology is also pursued as well as gene array analysis of the transcriptome. B cell malignancies is one focus in antibody and gene therapy projects as well as viral infection in molecular breeding projects. Dept. of Immunotechnology, Lund Univ., Sweden  http://www.immun.lth.se/  

Refers to any approach aimed at mobilizing or manipulating a patient's immune system to treat or cure disease. Although the term has been most often associated with therapies for established malignancies, immunotherapy is of increasing interest as an approach to arrest cancer at a much earlier stage. In addition as illustrated in the accompanying articles, immunotherapy is pertinent to the investigation and treatment of transplantation, autoimmunity, chronic inflammation, and infectious disease. Ralph M Steinman and Ira Mellman, Immunotherapy; Bewitched, Bothered and Bewildered No more. Science 305: 197- 200, 9 July 2004

The concept of using the immune system to treat disease, for example, developing a vaccine against cancer. Immunotherapy may also refer to the therapy of diseases caused by the immune system, allergies for example. NHGRI

Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. MeSH, 1973 

immunotoxins:  Semi-synthetic conjugates of various toxic molecules, including radioactive isotopes and bacterial or plant toxins, with specific immune substances such as immunoglobulins, monoclonal antibodies, and antigens. The antitumor or antiviral immune substance carries the toxin to the tumor or infected cell where the toxin exerts its poisonous effect. MeSH, 1990 Broader term: antibodies

Lead and candidate selection for Therapeutic proteins JANUARY 21-22, 2020, San Diego CA  The screenings and studies that comprise a company's lead and candidate selection funnel are an essential stage of biopharmaceutical R&D. Good selections not only ensure that the best quality molecules are chosen for advancement, but that these match target profile for efficacy, safety, and pharmacology. https://www.chi-peptalk.com/lead-candidate-selection

ligand: Pharmaceutical biology  ligand binding assays: Assays 

monoclonal antibodies: A single species of immunoglobulin molecules produced by culturing a single clone of a hybridoma cell. MAbs recognize only one chemical structure, i.e., they are directed against a single epitope of the antigenic substance used to raise the antibody. IUPAC Biotech

Antibodies produced by clones of cells such as those isolated after hybridization of activated B lymphocytes with neoplastic cells. These hybrids are often referred to as hybridomas. MeSH, 1982  Broader term: antibody; Related terms: clinical antibodies, cloning, hybridoma, fully humanized antibodies, polyclonal antibodies,  recombinant antibodies,  therapeutic antibodies, polyclonal antibodies 

Development of Therapeutic Monoclonal Antibody Products A Comprehensive Guide to CMC Activities from Clone to Clinic  Insight Pharma Reports 2017 As the pharmaceutical market in the United States and the rest of the world continues to expand, biopharmaceutical products have taken on increasing importance in the treatment of disease. Sales of monoclonal antibody products have grown from approximately $50 billion in 2010 to almost $90 billion in 2015, an approximately 1.8‑fold increase and represent approximately 58% of biopharmaceutical sales.  As more and more exciting monoclonal antibody products for treatment of cancer, autoimmune diseases, cardiovascular disease, and others are introduced, sales from new products approved in the coming years will drive the world-wide sales of monoclonal antibody products to approximately $110 billion by 2018 and nearly $150 billion by 2021. 

http://www.insightpharmareports.com/Therapeutic-Monoclonal-Antibodies/

multispecific antibodies: A classical antibody’s two arms will bind specifically to one antigen. Expertise in molecular design has led to novel antibody formats with additional features. One approach implies engineering multiple antigen binding domains into a single antibody molecule. These so-called bi-or multispecific antibodies combine two or more antigen-recognising elements into a single molecule, able to bind to two or more targets. Roche R*D https://www.roche.com/research_and_development/what_we_are_working_on/research_technologies/antibodies-at-roche.htm  Narrower term: Bispecific antibodies

next generation antibodies: New opportunities for antibody drugs may be possible by developing antibodies with novel mechanisms of action, such as those that induce tumour cell killing or receptor agonism.  Additional opportunities for antibody drugs are anticipated by overcoming existing obstacles to delivery, such as poorly accessible sites of action including the brain, lungs and gastrointestinal tract and perhaps ultimately the cytosol of cells. Bispecific and multispecific targeting with antibodies is enabling advances in immune cell recruitment, improvements in tissue selectivity and novel mechanistic approaches to agonism and transport. Targets that are currently not amenable to antibody approaches — the 'high-hanging fruit' — may become druggable in the future through continued innovation. Next generation antibody drugs: pursuit of the 'high-hanging fruit' Paul J. Carter  & Greg A. Lazar Nature Reviews Drug Discovery volume17, pages197–223 (2018)  https://www.nature.com/articles/nrd.2017.227

Oligonucleotide & Precision Therapeutics  March 17-18, 2020 Cambridge, MA reveals the latest strategies at the forefront of discovery, chemistry and delivery with in-depth sessions on new chemistries, novel delivery mechanisms and the most important preclinical and clinical advances. Leading oligonucleotide scientists deliver detailed case studies on antisense, RNA, aptamers and conjugates . https://www.optcongress.com/oligonucleotide

Oligonucleotide Discovery & Delivery  March 17-18, 2020 Cambridge, MA   | detailed case studies on antisense, RNA, aptamer and oligonucleotide conjugates  .https://www.optcongress.com/oligonucleotide

oligonucleotide therapeutics: In this review we address the development of oligonucleotide (ON) medicines from a historical perspective by listing the landmark discoveries in this field. The various biological processes that have been targeted and the corresponding ON interventions found in the literature are discussed together with brief updates on some of the more recent developments. Most ON therapies act through antisense mechanisms and are directed against various RNA species, as exemplified by gapmers, steric block ONs, antagomirs, small interfering RNAs (siRNAs), micro-RNA mimics, and splice switching ONs. However, ONs binding to Toll-like receptors and those forming aptamers have completely different modes of action. Similar to other novel medicines, the path to success has been lined with numerous failures, where different therapeutic ONs did not stand the test of time. Since the first ON drug was approved for clinical use in 1998, the therapeutic landscape has changed considerably, but many challenges remain until the expectations for this new form of medicine are met. However, there is room for cautious optimism. Oligonucleotide Therapies: The Past and the Present  Karin E. Lundin,^* Olof Gissberg, and C.I. Edvard Smith Hum Gene Ther. 2015 Aug 1; 26(8): 475–485.Published online 2015 Jul 8. doi:  10.1089/hum.2015.070  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4554547/

PEGS: the essential protein engineering summit  May 4-8, 2020 • Boston, MA  | Conference programs include protein and antibody engineering, cancer immunotherapy, oncology, and emerging therapeutics. https://www.pegsummit.com/


PEGS Europe  2019 Nov 18-22 Lisbon Portugal Conference programs include Engineering, Oncology, Analytical, Immunotherapy, Expression and Bispecifics.  https://www.pegsummiteurope.com/



PepTalk  January 20-24, 2020 • San Diego, CA | Conference programs include Protein Engineering and Development, Innovations in Discovery and Development, Antibody Therapeutics,  Formulation and Stability, Analytics & Impurities, Process Technologies & Purification, Biotherapeutic expression & production, Alternative expression & products.