10th antibody industrial symposium: new developments in antibody and adoptive cell therapies.

The annual "Antibody Industrial Symposium", co-organized by LabEx MAbImprove and MabDesign, held its 10th anniversary edition in Montpellier, France, on June 28-29, 2022. The meeting focused on new results and concepts in antibody engineering (naked, mono- or multi-specific, conjugated to drugs or radioelements) and also on new cell-based therapies, such as chimeric antigenic receptor (CAR)-T cells. The symposium, which brought together scientists from academia and industry, also addressed issues concerning the production of these molecules and cells, and the necessary steps to ensure a strong intellectual property protection of these new molecules and approaches. These two days of exchanges allowed a rich discussion among the various actors in the field of therapeutic antibodies.

[Therapeutic antibodies and related products: choosing the right structure for success]. / Anticorps thérapeutiques et dérivés : une palette de structures pour une pléthore d'indications. Quel format et quelle glycosylation choisir ? Pour quelles applications ?

Monoclonal antibodies (mAb) and related-products represent the fastest growing class of therapeutics in the biotechnological and pharmaceutical industry. In just as short as 20 years, more than 30 immunoglobulins (IgG) and derivatives have been approved in a wide range of indications (oncology, inflammation and auto-immunity, transplantation, angioplasty, hematology, ophthalmology, viral infections, allergy). The mAb structure toolbox contains mouse, chimeric, humanized and human antibodies from different isotypes (IgG1, 2 and 4), as well as IgG-related products (immunoconjugates, radio-immunoconjugates, Fab fragments, Fc-fusion proteins and peptides, bispecifics). Furthermore from a structural point of view, mAb glycosylation is linked to their production systems and may impact on their effector functions and immunogenicity. Based on the current knowledge, choosing the right antibody format, isotype and glycosylation profile are some of the key issues to address early during the lead selection.

[Protein scaffolds as alternatives to whole antibodies: from discovery research to clinical development]. / Ingénierie de charpentes protéiques comme alternative aux anticorps : de la recherche au développement clinique.

Recent advances in combinatorial protein engineering have made it possible to develop non-Ig protein scaffolds that can potentially substitute for most whole antibody-associated properties. These protein scaffolds display most of the binding properties associated with the variable domain of antibodies. In theory, many different natural human protein backbones are suitable to be used as recombinant templates for engineering ; in practice however, only a few have yielded the necessary properties to be translated into << druggable biologicals >>. Amongst these properties, potential broad specificities towards any kind of target, ease of production, small size, good tolerability and low immunogenicity are essential. Intellectual property is another key issue. In this review, a particular emphasis will be given to the most validated non-Ig scaffolds that have reached the clinical development phase.

[Bispecific antibodies, novel therapeutic candidates harnessing the immune system]. / Les anticorps et scaffold bispécifiques, des médicaments innovants en oncologie impliquant le ciblage des cellules immunitaires.

Over the past ten years, an increased knowledge of tumor biology and immunology allowed the design and development of novel therapeutic antibody and protein scaffold formats, where bispecific antibodies (Abs) play a major role. The latter molecules can (1) bring novel pharmacological properties through the co-engagement of two targets, (2) increase the safety profile as compared to a combination of two antibodies thanks to a targeted relocation to the tumor and (3) reduce development and manufacturing costs associated with single drug product. This review analyzes the different bispecific antibodies and scaffolds described in the field of immuno-oncology, their structure and major pharmacological and physico-chemical properties.

TITLE: Les anticorps et scaffold bispécifiques, des médicaments innovants en oncologie impliquant le ciblage des cellules immunitaires. ABSTRACT: Une connaissance approfondie de la biologie et de l'immunologie des tumeurs, mais aussi la conception de formats innovants d'anticorps et d'autres charpentes (ou scaffolds) protéiques ont permis de générer une véritable explosion de nouvelles molécules à visée thérapeutique au cours de ces 10 dernières années. Dans ce cadre, les anticorps bispécifiques (Abs) tiennent une place de choix. Ils permettent en effet, (1) d'apporter des propriétés biologiques et pharmacologiques nouvelles qui dépendent de l'engagement simultané des deux cibles, (2) d'améliorer le profil de sécurité par rapport à une combinaison d'anticorps en favorisant sa localisation tumorale en oncologie, et également (3) de combiner en une seule molécule les activités de deux anticorps conventionnels, réduisant ainsi les coûts de développement clinique et de fabrication. Cet article de revue a pour objectif d'analyser les différentes molécules bispécifiques décrites à ce jour dans le domaine de l'immuno-oncologie, et de présenter leurs différents formats et principales propriétés.

Functional responses and in vivo anti-tumour activity of h7C10: a humanised monoclonal antibody with neutralising activity against the insulin-like growth factor-1 (IGF-1) receptor and insulin/IGF-1 hybrid receptors.

A novel humanised monoclonal antibody (Mab, h7C10) was raised against the human insulin-like growth factor-1 receptor (IGF-1R); it exhibited potent inhibition of tumour growth in animal models. Further evaluation of its inhibitory activity at hybrid receptors (Hybrid-Rs) composed of the association between IGF-1R and insulin receptor (IR) was performed. Selective, potent and efficacious inhibition of [(125)I]IGF-1 binding as well as IGF-1- and IGF-2-mediated receptor phosphorylation was demonstrated at both IGF-1R and Hybrid-Rs, without activity at IR. Ligand-independent down-regulation of both IGF-1R and Hybrid-Rs was obtained upon long-term association with h7C10. In vivo evaluation was performed in a MDA-MB-231 xenograft mouse model, showing a 14-fold higher level of Hybrid-Rs as compared to IGF-1R. A more potent anti-tumoural response was obtained for h7C10 as compared to Mabs targeting solely IGF-1R or Hybrid-Rs. The herewith described neutralising properties of h7C10 as potent inhibitor of both IGF-1R and Hybrid-Rs are likely to participate in its anti-tumoural activities and maybe of interest for therapeutic applications.

Antibody Engineering & Therapeutics, the annual meeting of The Antibody Society December 7-10, 2015, San Diego, CA, USA.

The 26th Antibody Engineering & Therapeutics meeting, the annual meeting of The Antibody Society united over 800 participants from all over the world in San Diego from 6-10 December 2015. The latest innovations and advances in antibody research and development were discussed, covering a myriad of antibody-related topics by more than 100 speakers, who were carefully selected by The Antibody Society. As a prelude, attendees could join the pre-conference training course focusing, among others, on the engineering and enhancement of antibodies and antibody-like scaffolds, bispecific antibody engineering and adaptation to generate chimeric antigen receptor constructs. The main event covered 4 d of scientific sessions that included antibody effector functions, reproducibility of research and diagnostic antibodies, new developments in antibody-drug conjugates (ADCs), preclinical and clinical ADC data, new technologies and applications for bispecific antibodies, antibody therapeutics for non-cancer and orphan indications, antibodies to harness the cellular immune system, building comprehensive IgVH-gene repertoires through discovering, confirming and cataloging new germline IgVH genes, and overcoming resistance to clinical immunotherapy. The Antibody Society's special session focused on "Antibodies to watch" in 2016. Another special session put the spotlight on the limitations of the new definitions for the assignment of antibody international nonproprietary names introduced by the World Health Organization. The convention concluded with workshops on computational antibody design and on the promise and challenges of using next-generation sequencing for antibody discovery and engineering from synthetic and in vivo libraries.

Differential ion current activation by human 5-HT(1A) receptors in Xenopus oocytes: evidence for agonist-directed trafficking of receptor signalling.

The subject of the present study was the functional and pharmacological characterization of human 5-HT(1A) receptor regulation of ion channels in Xenopus oocytes. Activation of the heterologously expressed human 5-HT(1A) receptor induced two distinct currents in Xenopus oocytes, consisting of a smooth inward current (I(smooth)) and an oscillatory calcium-activated chloride current, I(Cl(Ca)). 5-HT(1A) receptor coupling to both ionic responses as well as to co-expressed inward rectifier potassium (GIRK) channels was pharmacologically characterized using 5-HT(1A) receptor agonists. The relative order of efficacy for activation of GIRK current was 5-HT approximately F 13714 approximately L 694,247 approximately LY 228,729>flesinoxan approximately (+/-)8-OH-DPAT. In contrast, flesinoxan and (+/-)8-OH-DPAT typically failed to activate I(Cl(Ca)). The other ligands behaved as full or partial agonists, exhibiting an efficacy rank order of 5-HT approximately L 694,247>F 13714 approximately LY 228,729. The pharmacological profile of I(smooth) activation was completely distinct: flesinoxan and F 13714 were inactive and rather exhibited an inhibition of this current. I(smooth) was activated by the other agonists with an efficacy order of L 694,247>5-HT approximately LY 228,729>(+/-)8-OH-DPAT. Moreover, activation of I(smooth) was not affected by application of pertussis toxin or the non-hydrolyzable GDP-analogue, guanosine-5'-O-(2-thio)-diphosphate (GDP betaS), suggesting a GTP binding protein-independent pathway. Together, these results suggest the existence of distinct and agonist-specific signalling states of this receptor.

Pharmacological analysis of a dopamine D(2Short):G(alphao) fusion protein expressed in Sf9 cells.

A dopamine D(2Short) receptor:G(alphao) fusion protein was expressed in Sf9 cells using the baculovirus expression system. [(3)H]Spiperone bound to D(2Short):G(alphao) with a pK(d) approximately 10. Dopamine stimulated the binding of [(35)S]guanosine-5'-O-(3-thio)triphosphate (GTPgammaS) to D(2Short):G(alphao) expressed with Gbeta(1)gamma(2) (E(max)>460%; pEC(50) 5.43+/-0.06). Most of the putative D(2) antagonists behaved as inverse agonists (suppressing basal [(35)S]GTPgammaS binding) at D(2Short):G(alphao)/Gbeta(1)gamma(2) although (-)-sulpiride and ziprasidone were neutral antagonists. Competition of [(3)H]spiperone binding by dopamine and 10,11-dihydroxy-N-n-propylnorapomorphine revealed two binding sites of different affinities, even in the presence of GTP (100 micro M). The D(2Short):G(alphao) fusion protein is therefore a good model for characterising D(2) receptors.

Endogenous RGS proteins facilitate dopamine D(2S) receptor coupling to G(alphao) proteins and Ca2+ responses in CHO-K1 cells.

The role of RGS proteins on dopaminergic D2S receptor (D2SR) signalling was investigated in Chinese hamster ovary (CHO)-K1 cells, using recombinant RGS protein- and PTX-insensitive G alphao proteins. Dopamine-mediated [35S]GTPgammaS binding was attenuated by more than 60% in CHO-K1 D2SR cells coexpressing a RGS protein- and PTX-insensitive G(alphao)Gly184Ser:Cys351Ile protein versus cells coexpressing a similar amount of PTX-insensitive G alphaoCys351Ile protein. Dopamine-agonist-mediated Ca2+ responses were dependent on the coexpression with a G alphao Cys351Ile protein and were fully abolished upon coexpression with a G alphaoGly184Ser:Cys351Ile protein. These results suggest that interactions between the G alphao protein and RGS proteins are involved in efficient D2SR signalling.

Molecular cloning and expression of the porcine trigeminal ganglion cDNA encoding a 5-ht(1F) receptor.

Using a combination of reverse transcription polymerase chain reaction (RT-PCR) and inverse-PCR techniques, we amplified, cloned and sequenced a full-length porcine 5-hydroxytryptamine 1F (5-ht(1F)) receptor complementary DNA (cDNA) derived from porcine trigeminal ganglion. Sequence analysis revealed 1101 base pairs (bp) encoding an open reading frame of 366 amino acids showing a high similarity (>90%) with the 5-ht(1F) receptor sequences from other species, including human. The recombinant porcine 5-ht(1F) receptor was expressed in African green monkey kidney cell lines (COS-7 cells) and its ligand binding profile was determined using [3H]5-HT. The affinities of several agonists (LY334370 (5-(4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole fumarate)>CP122638 (N-methyl-3 [pyrrolidin 2(R)-yl methyl]-1H-indol-5-ylmethyl sulphonamide)=naratriptan =5HT>eletriptan>sumatriptan>frovatriptan =avitriptan>dihydroergotamine>zolmitriptan>5-carboxamidotryptamine>rizatriptan>alniditan=donitriptan>L694247 (2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indole-3-yl] ethylamine) and putative antagonists (methiothepin>GR127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl 4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide hydrochloride)>ritanserin>SB224289 (2,3,6,7-tetrahydro-1'-methyl-5-[2'-methyl-4'(5-methyl-1,2,4-oxadiazol-3-yl) biphenyl-4-carbonyl] furo [2,3-f] indole-3-spiro-4'-piperidine hydrochloride)>BRL155572 ([1-(3-chlorophenyl)-4-[3,3-diphenyl (2-(S,R) hydroxypropanyl)piperazine] hydrochloride)>ketanserin=pindolol) correlated highly with those described for the recombinant human 5-ht(1F) receptor (Spearman correlation coefficient; r(s)=0.942). Nevertheless, as compared to the human homologue, some triptans (i.e. sumatriptan, zolmitriptan and rizatriptan) displayed a 10- to 15-fold lower affinity for the porcine 5-ht(1F) receptor. Using RT-PCR technique, the expression of porcine 5-ht(1F) receptor mRNA was observed in cerebral cortex, trigeminal ganglion and several blood vessels, but not in skeletal muscles. In conclusion, we have cloned and established the amino acid sequence and ligand binding profile of the porcine 5-ht(1F) receptor as well as the distribution of its mRNA. This information may be helpful in exploring the role of 5-ht(1F) receptor in physiological processes and diseases, such as migraine.

Modulation of 5-HT(1A) receptor-mediated Ca(2+) responses by co-expression with various recombinant G(alpha) proteins in CHO-K1 cells.

The ability of the human 5-HT(1A) receptor to activate different recombinant G(alpha) proteins was investigated in CHO-K1 cells by monitoring 5-HT ligand-mediated Ca(2+) responses upon co-expression with either G(alphaq), G(alpha15) or chimeric G(alphaq/i3) proteins. Each G(alpha) protein yielded a typical 5-HT-dependent Ca(2+) response with different kinetic parameters both for the onset-time of maximal Ca(2+) response (21 to 30 s) and time-dependent attenuation (43 to 73% of residual activity at 1 min upon peak Ca(2+) response). Pertussis toxin-treatment fully abolished the Ca(2+) responses mediated by both the endogenous G(i/o) and the chimeric-PTX-sensitive G(alphaq/i3) proteins. In contrast, Ca(2+) responses driven by recombinant G(alphaq) and G(alpha15) proteins were decreased by PTX, respectively by 52% and 35%, corresponding to the level of endogenous G protein activation. The pharmacology of the 5-HT ligand-mediated Ca(2+) responses was highly affected by both the presence and nature of the co-expressed G(alpha) protein. This influence was more pronounced for the partial agonists L 694247, 8-OH-DPAT, flesinoxan and buspirone in contrast to ipsapirone. The G(alpha) protein rank order for apparent increase of ligands' intrinsic activity was: G(alphaq)

9th annual European Antibody Congress, November 11-13, 2013, Geneva, Switzerland.

The annual European Antibody Congress (EAC) has traditionally been the key event for updates on critical scientific advances in the antibody field, and 2013 was no exception. Organized by Terrapinn, the well-attended meeting featured presentations on considerations for developing antibodies and antibody-like therapeutics, with separate tracks for antibody-drug conjugates, naked antibodies, and multispecific antibodies or protein scaffolds. The overall focus of the EAC was current approaches to enhance the functionality of therapeutic antibodies or other targeted proteins, with the ultimate goal being improvement of the safety and efficacy of the molecules as treatments for cancer, immune-mediated disorders and other diseases. Roundtable discussion sessions gave participants opportunities to engage in group discussions with industry leaders from companies such as Genmab, Glenmark Pharmaceuticals, MedImmune, Merrimack Pharmaceuticals, and Pierre Fabre. As the 2013 EAC was co-located with the World Biosimilar Congress, participants also received an update on European Medicines Agency guidelines and thoughts on the future direction and development of biosimilar antibodies in the European Union.

8(th) Annual European Antibody Congress 2012: November 27-28, 2012, Geneva, Switzerland.

The 8th European Antibody Congress (EAC), organized by Terrapin Ltd., was again held in Geneva, Switzerland, following on the tradition established with the 4th EAC. The new agenda format for 2012 included three parallel tracks on: (1) naked antibodies; (2) antibody drug conjugates (ADCs); and (3) bispecific antibodies and alternative scaffolds. The meeting started and closed with three plenary lectures to give common background and to share the final panel discussion and conclusions. The two day event included case studies and networking for nearly 250 delegates who learned of the latest advances and trends in the global development of antibody-based therapeutics. The monoclonal antibody track was focused on understanding the structure-function relationships, optimization of antibody design and developability, and processes that allow better therapeutic candidates to move through the clinic. Discussions on novel target identification and validation were also included. The ADC track was dedicated to evaluation of the ongoing success of the established ADC formats alongside the rise of the next generation drug-conjugates. The bispecific and alternative scaffold track was focused on taking stock of the multitude of bispecific formats being investigated and gaining insight into recent innovations and advancements. Mechanistic understanding, progression into the clinic and the exploration of multispecifics, redirected T cell killing and alternative scaffolds were extensively discussed. In total, nearly 50 speakers provided updates of programs related to antibody research and development on-going in the academic, government and commercial sectors.

Novel protein scaffolds as emerging therapeutic proteins: from discovery to clinical proof-of-concept.

Recent advances in combinatorial protein engineering have made it possible to develop immunoglobulin (Ig)-based and non-Ig protein scaffolds that can potentially substitute for most whole antibody-associated properties and currently translate into biologicals with drug-like properties. During the past 10 years, the most validated scaffolds have reached the clinical development phase and, recently, one of them [Kalbitor(®) (Dyax)] has made it to the market, making these alternative scaffold proteins viable drug candidates in a post-antibody landscape. Interestingly, several scaffolds include an immune-active component as part of their therapeutic mode of action, which yielded spectacular clinical efficacy in some hematological malignancies. Here, we review the most recent clinical advances and analyze their benefits for patients.

IBC's 22nd Annual Antibody Engineering and 9th Annual Antibody Therapeutics International Conferences and the 2011 Annual Meeting of The Antibody Society, December 5-8, 2011, San Diego, CA.

The 22nd Annual Antibody Engineering and 9th Annual Antibody Therapeutics international conferences, and the 2011 Annual Meeting of The Antibody Society, organized by IBC Life Sciences with contributions from The Antibody Society and two Scientific Advisory Boards, were held December 5-8, 2011 in San Diego, CA. The meeting drew ~800 participants who attended sessions on a wide variety of topics relevant to antibody research and development. As a preview to the main events, a pre-conference workshop held on December 4, 2011 focused on antibodies as probes of structure. The Antibody Engineering Conference comprised eight sessions: (1) structure and dynamics of antibodies and their membrane receptor targets; (2) model-guided generation of binding sites; (3) novel selection strategies; (4) antibodies in a complex environment: targeting intracellular and misfolded proteins; (5) rational vaccine design; (6) viral retargeting with engineered binding molecules; (7) the biology behind potential blockbuster antibodies and (8) antibodies as signaling modifiers: where did we go right, and can we learn from success? The Antibody Therapeutics session comprised five sessions: (1)Twenty-five years of therapeutic antibodies: lessons learned and future challenges; (2) preclinical and early stage development of antibody therapeutics; (3) next generation anti-angiogenics; (4) updates of clinical stage antibody therapeutics and (5) antibody drug conjugates and bispecific antibodies.

6th Annual European Antibody Congress 2010: November 29-December 1, 2010, Geneva, Switzerland.

The 6th European Antibody Congress (EAC), organized by Terrapinn Ltd., was held in Geneva, Switzerland, which was also the location of the 4th and 5th EAC. As was the case in 2008 and 2009, the EAC was again the largest antibody congress held in Europe, drawing nearly 250 delegates in 2010. Numerous pharmaceutical and biopharmaceutical companies active in the field of therapeutic antibody development were represented, as were start-up and academic organizations and representatives from the US Food and Drug Administration FDA. The global trends in antibody research and development were discussed, including success stories of recent marketing authorizations of golimumab (Simponi®) and canakinumab (Ilaris®) by Johnson & Johnson and Novartis, respectively, updates on antibodies in late clinical development (obinutuzumab/GA101, farletuzumab/MORAb-003 and itolizumab/T1 h, by Glycart/Roche, Morphotek and Biocon, respectively) and success rates for this fast-expanding class of therapeutics (Tufts Center for the Study of Drug Development). Case studies covering clinical progress of girentuximab (Wilex), evaluation of panobacumab (Kenta Biotech), characterization of therapeutic antibody candidates by protein microarrays (Protagen), antibody-drug conjugates (sanofi-aventis, ImmunoGen, Seattle Genetics, Wyeth/Pfizer), radio-immunoconjugates (Bayer Schering Pharma, Université de Nantes) and new scaffolds (Ablynx, AdAlta, Domantis/GlaxoSmithKline, Fresenius, Molecular Partners, Pieris, Scil Proteins, Pfizer, University of Zurich) were presented. Major antibody structural improvements were showcased, including the latest selection engineering of the best isotypes (Abbott, Pfizer, Pierre Fabre), hinge domain (Pierre Fabre), dual antibodies (Abbott), IgG-like bispecific antibodies (Biogen Idec), antibody epitope mapping case studies (Eli Lilly), insights in FcγRII receptor (University of Cambridge), as well as novel tools for antibody fragmentation (Genovis). Improvements of antibody druggability (Abbott, Bayer, Pierre Fabre, Merrimack, Pfizer), enhancing IgG pharmacokinetics (Abbott, Chugai), progress in manufacturing (Genmab, Icosagen Cell Factory, Lonza, Pierre Fabre) and the development of biosimilar antibodies (Biocon, Sandoz, Triskel) were also discussed. Last but not least, identification of monoclonal antibodies (mAbs) against new therapeutic targets (Genentech, Genmab, Imclone/Lilly, Vaccinex) including Notch, cMet, TGFbRII, SEMA4D, novel development in immunotherapy and prophylaxis against influenza (Crucell), anti-tumor activity of immunostimulatory antibodies (MedImmune/Astra Zeneca) and translations to clinical studies including immunogenicity issues (Amgen, Novartis, University of Debrecen) were presented.

GlycoFi's technology to control the glycosylation of recombinant therapeutic proteins.

IMPORTANCE OF THE FIELD: Therapeutic properties of many glycoproteins strongly depend on the composition of their glycans. Most of the current approved glycoproteins are produced in mammalian cell lines, which yield mixture of different glycoforms close to the human one but not fully identical. Glyco-engineering is being developed as a method to control the composition of carbohydrates. Many alternative glycoprotein productions systems are actively investigated including new-engineered yeast strains, as developed by GlycoFi, a biotech company fully owned by Merck & Co. since 2006. AREAS COVERED IN THIS REVIEW: The objectives of this opinion paper is to present a comprehensive overview of the technological breakthrough developed by GlycoFi to produce recombinant human proteins with controlled glycosylation patterns in yeast, in comparison to other glyco-engineering technologies and to discuss the application to large-scale manufacturing of biologicals. WHAT THE READER WILL GAIN: Research papers and recent review articles on protein glycosylation and glyco-engineering, and in-depth search of the bibliography by the GlycoFi's research team, summary of recent meetings discussing the biosimilar topic were analyzed by the authors and will help the reader to gain insight in the field. TAKE HOME MESSAGE: The glyco-engineering technology of the Pichia pastoris N-glycosylation pathway developed by GlycoFi allows producing human proteins with complex N-glycosylation modifications, which are similar to the ones performed in human. Moreover, more homogeneous glycosylation patterns are observed, as opposed to the large heterogeneity of glycan moieties that are found naturally in mammals or in other production systems such as Chinese hamster ovary and NS0 cell lines. These properties associated with the perspective to industrialize the manufacturing process of Pichia makes it a very promising expression system to produce large-scale batches of therapeutics at a lower cost.

Strategies and challenges for the next generation of therapeutic antibodies.

Antibodies and related products are the fastest growing class of therapeutic agents. By analysing the regulatory approvals of IgG-based biotherapeutic agents in the past 10 years, we can gain insights into the successful strategies used by pharmaceutical companies so far to bring innovative drugs to the market. Many challenges will have to be faced in the next decade to bring more efficient and affordable antibody-based drugs to the clinic. Here, we discuss strategies to select the best therapeutic antigen targets, to optimize the structure of IgG antibodies and to design related or new structures with additional functions.

The next generation of antibody-drug conjugates comes of age.

Monoclonal antibodies (mAbs) and derivatives are currently the fastest growing class of therapeutic molecules. More than 30 G-type immunoglobulins (IgG) and related agents have been approved over the past 25 years mainly for cancers and inflammatory diseases. In oncology, mAbs are often combined with cytotoxic drugs to enhance their therapeutic efficacy. Alternatively, small anti-neoplastic molecules can be chemically conjugated to mAbs, used both as carriers (increased half-life) and as targeting agents (selectivity). Potential benefits of antibody-drug conjugates (ADCs), strategies, and development challenges are discussed in this review. Several examples of ADCs are presented with emphasis on three major molecules currently in late clinical development as well as next generation thio-mAbs conjugates with improved therapeutic index.

Keystone Symposium on Antibodies as Drugs: March 27-April 1, 2009, Whistler, BC CA.

The symposium on Antibodies as Drugs, organized by Keystone Symposia and chaired by J. Marks, (University of California Los Angeles, USA), E.S. Ward (University of Texas Southwestern Medical Center, USA) and L. Weiner (Georgetown University Medical Center, USA), was held in Whistler, British Columbia. This Canadian Rockies village, which will host the 2010 Olympic Games, served as an enchanting backdrop to the meeting. The more than 350 speakers and attendees included scientists from major pharmaceutical firms, e.g., Abbott, MedImmune/Astra Zeneca, Bristol-Myers Squibb, Merck & Co., Pfizer, Sanofi-Aventis, Schering, GlaxoSmithKline, Eli Lilly, Hoffmann LaRoche, Novartis, Wyeth, and biotechnology companies, e.g., Ablynx, Medarex, Morphosys, GenMab, Amgen, Genentech, ImmunoGen, Agensys, Domantis, Biogen Idec, Centocor, LFB, Micromet, PDL Biopharma, Borean Pharma, Dyax Corp., Symphogen and Syntonix. Academic research groups at Imperial College London, University of Oxford, ETH Zürich, Scripps, Institute Cochin, Karolinska Institute, Utrecht University, Harvard Medical School, Massachusetts Institute of Technology, Baylor College, Paul Ehrlich Institute, University of California San Francisco, University of California San Diego, University of Nantes, University of Tours and Ludwig Institute were also represented, as were regulatory authorities, including the US Food and Drug Administration, National Institutes of Health and the Public Health Agency of Canada). The meeting was very interactive and included thoughtful exchanges during the different sessions and networking events.