Antibody Engineering & Therapeutics 2015: The Antibody Society's annual meeting December 7–10, 2015, San Diego,CA

Antibody Engineering & Therapeutics, the annual meeting of The Antibody Society, will be held in San Diego, CA in early December 2015. In this meeting preview, the chairs provide their thoughts on the importance of their session topics, which include 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, overcoming resistance to clinical immunotherapy, and building comprehensive IGVH-gene repertoires through discovering, confirming and cataloging new germline IGVH genes. The Antibody Society's special session will focus on “Antibodies to watch” in 2016, which are a subset of the nearly 50 antibodies currently in Phase 3 clinical studies. Featuring over 100 speakers in total, the meeting will commence with keynote presentations by Erica Ollmann Saphire (The Scripps Research Institute), Wayne A. Marasco (Dana-Farber Cancer Institute/Harvard Medical School), Joe W. Gray (Oregon Health & Science University), and Anna M. Wu (University of California Los Angeles), and it will conclude with workshops on the promise and challenges of using next-generation sequencing for antibody discovery and engineering from synthetic and in vivo libraries and on computational antibody design.     

Antibody Engineering & Therapeutics 2015: The Antibody Society's annual meeting December 7–10, 2015, San Diego,CA

Antibody Engineering & Therapeutics, the annual meeting of The Antibody Society, will be held in San Diego, CA in early December 2015. In this meeting preview, the chairs provide their thoughts on the importance of their session topics, which include 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, overcoming resistance to clinical immunotherapy, and building comprehensive IGVH-gene repertoires through discovering, confirming and cataloging new germline IGVH genes. The Antibody Society''s special session will focus on “Antibodies to watch” in 2016, which are a subset of the nearly 50 antibodies currently in Phase 3 clinical studies. Featuring over 100 speakers in total, the meeting will commence with keynote presentations by Erica Ollmann Saphire (The Scripps Research Institute), Wayne A. Marasco (Dana-Farber Cancer Institute/Harvard Medical School), Joe W. Gray (Oregon Health & Science University), and Anna M. Wu (University of California Los Angeles), and it will conclude with workshops on the promise and challenges of using next-generation sequencing for antibody discovery and engineering from synthetic and in vivo libraries and on computational antibody design.     

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 22^nd Annual Antibody Engineering and 9^th 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 Conference 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.Key words: antibody engineering, antibody therapeutics, antibody-drug conjugates, bispecific antibodies, computational design, antibody-antigen structure, vaccine design     

IBC’s 23rd Annual Antibody Engineering, 10th Annual Antibody Therapeutics International Conferences and the 2012 Annual Meeting of The Antibody Society

The 23rd Annual Antibody Engineering, 10th Annual Antibody Therapeutics international conferences, and the 2012 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 3–6, 2012 in San Diego, CA. The meeting drew over 800 participants who attended sessions on a wide variety of topics relevant to antibody research and development. As a prelude to the main events, a pre-conference workshop held on December 2, 2012 focused on intellectual property issues that impact antibody engineering. The Antibody Engineering Conference was composed of six sessions held December 3–5, 2012: (1) From Receptor Biology to Therapy; (2) Antibodies in a Complex Environment; (3) Antibody Targeted CNS Therapy: Beyond the Blood Brain Barrier; (4) Deep Sequencing in B Cell Biology and Antibody Libraries; (5) Systems Medicine in the Development of Antibody Therapies/Systematic Validation of Novel Antibody Targets; and (6) Antibody Activity and Animal Models. The Antibody Therapeutics conference comprised four sessions held December 4–5, 2012: (1) Clinical and Preclinical Updates of Antibody-Drug Conjugates; (2) Multifunctional Antibodies and Antibody Combinations: Clinical Focus; (3) Development Status of Immunomodulatory Therapeutic Antibodies; and (4) Modulating the Half-Life of Antibody Therapeutics. The Antibody Society’s special session on applications for recording and sharing data based on GIATE was held on December 5, 2012, and the conferences concluded with two combined sessions on December 5–6, 2012: (1) Development Status of Early Stage Therapeutic Antibodies; and (2) Immunomodulatory Antibodies for Cancer Therapy.     

IBC's 21st Annual Antibody Engineering and 8th Annual Antibody Therapeutics International Conferences and 2010 Annual Meeting of The Antibody Society: December 5–9, 2010, San Diego,CA USA

The 21^st Annual Antibody Engineering and 8^th Annual Antibody Therapeutics international conferences, and the 2010 Annual Meeting of The Antibody Society, organized by IBC Life Sciences with contributions from The Antibody Society and two Scientific Advisory Boards, was held December 5–9, 2010 in San Diego, CA. The conferences featured over 100 presentations and 100 posters, and included a pre-conference workshop on deep-sequencing of antibody genes. The total number of delegates exceeded 800, which set a new attendance record for the conference.The conferences were organized with a focus on antibody engineering only on the first day and a joint engineering/therapeutics session on the last day. Delegates could select from presentations that occurred in two simultaneous sessions on days 2 and 3. Day 1 included presentations on neutralizing antibodies and the identification of vaccine targets, as well as a historical overview of 20 years of phage display utilization. Topics presented in the Antibody Engineering sessions on day 2 and 3 included antibody biosynthesis, structure and stability; antibodies in a complex environment; antibody half-life; and targeted nanoparticle therapeutics. In the Antibody Therapeutics sessions on days 2 and 3, preclinical and early stage development and clinical updates of antibody therapeutics, including TRX518, SYM004, MM111, PRO140, CVX-241, ASG-5ME, U3-1287 (AMG888), R1507 and trastuzumab emtansine, were discussed and perspectives were provided on the development of biosimilar and biobetter antibodies, including coverage of regulatory and intellectual property issues. The joint engineering/therapeutics session on the last day focused on bispecific and next-generation antibodies. Summaries of most of the presentations are included here, but, due to the large number of speakers, it was not possible to include summaries for every presentation.Delegates enjoyed the splendid views of the San Diego Bay and proximity to the Gaslamp Quarter provided by the venue. The 22^nd Annual Antibody Engineering and 9th Annual Antibody Therapeutics conferences, and the 2011 Annual Meeting of The Antibody Society, are planned for December 5–8, 2011 at the same location in San Diego, and will include two two-day short courses on Introduction to Antibody Engineering and Protein Characterization for Biotechnology Product Development.Key words: antibody engineering, antibody therapeutics, phage display, biosimilar antibodies

• MAbs. 2011 Mar-Apr; 3(2): 133–152.
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• Day 1: December 6, 2010 Antibody Engineering

2011 Mar-Apr; 3(2): 133–152. Published online 2011 Mar 1. doi: 10.4161/mabs.3.2.14939

Day 1: December 6, 2010 Antibody Engineering

Samantha O Arnett Copyright and License information DisclaimerCopyright notice     

World Bispecific Antibody Summit,September 27–28, 2011, Boston,MA

With more than 30 therapeutic monoclonal antibodies (mAbs) approved and annual global sales of the products at ~$50 billion in 2010, these products have proven to be successful in many ways. Nevertheless, there is room for improvement in performance, and substantial unmet medical needs remain. As a consequence, numerous organizations are devoting resources to engineering novel mAbs such as bispecific antibodies that have increased functionality compared with unmodified IgG molecules. The World Bispecific Antibody Summit, organized by Hanson Wade, drew over 100 participants to Boston to discuss engineering novel bispecific antibodies, generating lead candidates and clinical study and commercialization of the molecules. Approaches such as the trifunctional antibody (TRION), dual variable domain-Ig (Abbott), two-in-one (Genentech), dual affinity retargeting (MacroGenics), kappa-lambda body (NovImmune), bispecific T-cell engager (Micromet) and chemical generation (CovX/Pfizer) were discussed in detail. In addition, posters describing bispecific Affibody® molecules for targeting of EGFR and HER2 (Affibody), T-cell receptor based bi-specifics that target HLA-peptides (Immunocore), a novel mAb-Fv bispecific antibody format utilizing Fc region (Xencore), generation of a tetravalent bispecific antibody against IL4 and IL13 for the treatment of idiopathic pulmonary fibrosis (Sanofi), Combining Affibody® molecules and the Albumod? technology to create long acting multispecific protein therapeutics (Royal Institute of Technology, Affibody) and COVA301 as a highly potent bispecific inhibitor of IL-17A and TNF-α (Covagen) were presented.     

World Bispecific Antibody Summit,September 27–28, 2011, Boston,MA

With more than 30 therapeutic monoclonal antibodies (mAbs) approved and annual global sales of the products at ∼$50 billion in 2010, these products have proven to be successful in many ways. Nevertheless, there is room for improvement in performance, and substantial unmet medical needs remain. As a consequence, numerous organizations are devoting resources to engineering novel mAbs such as bispecific antibodies that have increased functionality compared with unmodified IgG molecules. The World Bispecific Antibody Summit, organized by Hanson Wade, drew over 100 participants to Boston to discuss engineering novel bispecific antibodies, generating lead candidates and clinical study and commercialization of the molecules. Approaches such as the trifunctional antibody (TRION), dual variable domain-Ig (Abbott), two-in-one (Genentech), dual affinity retargeting (MacroGenics), kappa-lambda body (NovImmune), bispecific T-cell engager (Micromet) and chemical generation (CovX/Pfizer) were discussed in detail. In addition, posters describing bispecific Affibody^® molecules for targeting of EGFR and HER2 (Affibody), T-cell receptor based bi-specifics that target HLA-peptides (Immunocore), a novel mAb-Fv bispecific antibody format utilizing Fc region (Xencore), generation of a tetravalent bispecific antibody against IL4 and IL13 for the treatment of idiopathic pulmonary fibrosis (Sanofi), Combining Affibody^® molecules and the AlbumodTM technology to create long acting multispecific protein therapeutics (Royal Institute of Technology, Affibody) and COVA301 as a highly potent bispecific inhibitor of IL-17A and TNFα (Covagen) were presented.Key words: bispecific antibodies, antibody engineering, therapeutic antibodies     

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.     

4th European Antibody Congress 2008: December 1–3, 2008, Geneva,Switzerland

The Fourth European Antibody meeting, organized by Terrapin Ltd., was held in Geneva, a center of the European biopharmaceutical industry. Merck-Serono, NovImmune, Pierre Fabre and Therapeomic are located nearby, as are R&D centers of Boehringer-Ingelheim, Novartis, Roche and Sanofi-Aventis. Over 40 speakers and more than 200 delegates attended the event. Companies represented included Abbott, Ablynx, Adnexus/ BMS, Astra-Zeneca/ CAT/ Medimmune, BiogenIdec, BioRad, Centocor (Johnson & Johnson), Crucell/DSM, Domantis, Dyax, Genmab, Genzyme, Glycart/ Roche, Haptogen, Immunogen, Kyowa-Kirin, LFB, Medarex, Merck-Serono, Micromet, Novartis, Pierre Fabre Laboratories, Roche, Sanofi-Aventis, Seattle-Genetics, Transgene, UCB Celltech and Wyeth. Other attendees included those based in academe or government (University of Amsterdam, University of Zurich, Univeristy Hospital-Lyon, Ecole Polytechnique Federale de Lausanne, INSERM, Tufts University, US National Institutes of Health), consultants, and patent attorneys (Edwards, Angell, Palmer & Dodge). The meeting was very interactive and included exchanges during the many scheduled networking times (exhibitions, speed-networking, lunches and evening receptions). The first day of the three day conference was dedicated to advances in understanding antibody structure-function relationships. Challenges and opportunities in antibody development were the focus of the second day and the third day featured discussion of innovative antibodies and antibody alternatives.

• MAbs. 2009 Mar-Apr; 1(2): 93–103.
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• December 1, 2008 Day 1, Therapeutic antibodies: Advances in dissecting structure-function relationships

MAbs. 2009 Mar-Apr; 1(2): 93–103.

December 1, 2008 Day 1, Therapeutic antibodies: Advances in dissecting structure-function relationships

Alain BeckAuthor information Article notes Copyright and License information DisclaimerDepartment of Physico-Chemistry; Center of Immunology Pierre Fabre; Saint-Julien-en-Genevois, FranceCorresponding author.Correspondence to: Alain Beck; Centre d''Immunologie Pierre Fabre; 5 avenue Napoleon III; Saint-Julien-en-Genevois 74160 France; Email: moc.erbaferreip@kceb.nialaReceived 2009 Jan 20; Accepted 2009 Jan 20.Copyright © 2009 Landes BioscienceThe chairman, Alain Beck (Centre d''Immunologie Pierre Fabre), opened the meeting with the following remarks: Monoclonal antibodies (mAbs) and related-products (immunoconjugates, radioimmuno-conjugates, Fab fragments and Fc-fusion proteins) are the fastest growing class of pharmaceuticals, with nearly 30 products currently approved for a wide range of indications.^3,14 In just the last three years, six new antibodies and derivatives have reached the market. These included molecules that are novel formats, as well as first in class drugs in new therapeutic indications. In 2006, panitumumab (Vectibix) was the first fully human IgG2 mAb generated by immunization of humanized transgenic mice and the second anti-EGFR mAb to gain approval. Also in 2006, ranibizumab (Lucentis), the first E. coli-produced Fab fragment and the first affinity matured antibody, was approved as a treatment age-related macular degeneration. Later, tocilizumab (Actemra) a conventional IgG1, but directed against a new target (IL-6R), was registered in Japan; BLAs are pending both in the US and in Europe. In 2007, eculizumab (Soliris) was approved for paroxysmal nocturnal hemoglobinuria. Eculizumab was constituted by an original IgG2/4 hybrid format, and is unable to bind Fc receptors or activate the complement cascade. In 2008, rinolacept (Arcalyst), an IL-1R-Fc fusion protein also called IL-1 trap, was registered for cryopyrin-associated periodic syndromes. Also in 2008, certolizumab pegol (Cimzia) became the first PEGylated Fab fragment to gain approval. The product, indicated for Crohn disease, is produced in E. coli and conjugated to large PEG residues (40 kDa). Interestingly, from a structure-function standpoint, certolizumab was crystallized and the 3D model of this original PEG-Fab was recently reported.⁴ In addition to these six new antibody or antibody-related product approvals, the first two biosimilar antibodies, Reditux (a copy of rituximab developed by Dr Reddy) and Clotinab (a biogeneric of abciximab developed by ISU ABXIS), were recently launched in India and in South Korea, respectively. Active discussions are ongoing regarding whether such generic biopharmaceuticals may also be approved in Europe, following approval of other glycoproteins such as erythropoietin.¹⁶     

Expression,Purification, and Evaluation of Anti-IL-2Rα Antibody Secreted by Leishmania tarentolae

International Journal of Peptide Research and Therapeutics - Producing a functional anti-IL-2Rα antibody in Leishmania tarentolae, a trypanosomatid protozoan non-pathogenic to human, is a...     

7th Annual European Antibody Congress 2011: November 29–December 1, 2011, Geneva,Switzerland

The 7^th European Antibody Congress (EAC), organized by Terrapin Ltd., was again held in Geneva, Switzerland, following on the tradition established with the 4^th EAC. The 2011 version of the EAC was attended by nearly 250 delegates who learned of the latest advances and trends in the global development of antibody-based therapeutics. The first day focused on advances in understanding structure-function relationships, choosing the best format, glycoengineering biobetter antibodies, improving the efficacy and drugability of mAbs and epitope mapping. On the second day, the discovery of novel targets for mAb therapy, clinical pipeline updates, use of antibody combinations to address resistance, generation and identification of mAbs against new targets and biosimilar mAb development were discussed. Antibody-drug conjugates, domain antibodies and new scaffolds and bispecific antibodies were the topics of the third day. In total, nearly 50 speakers provided updates of programs related to antibody research and development on-going in the academic, government and commercial sectors.Key words: therapeutic antibodies, antibody-drug conjugates, protein scaffolds, bispecific antibodies, biosimilar antibodies     

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

The 6^th European Antibody Congress (EAC), organized by Terrapinn Ltd., was held in Geneva, Switzerland, which was also the location of the 4^th and 5^th EAC.^1,2 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, TGFβRII, 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.Key words: therapeutic antibodies, antibody-drug conjugates, protein scaffolds, biosimilars, bioproduction

• MAbs. 2011 Mar-Apr; 3(2): 111–132.
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• Day 1: November 29, 2010

2011 Mar-Apr; 3(2): 111–132. Published online 2011 Mar 1. doi: 10.4161/mabs.3.2.14788

Day 1: November 29, 2010

Alain Beck Copyright and License information DisclaimerCopyright notice The EAC chairman, Alain Beck (Centre d''Immunologie Pierre Fabre), opened the meeting with a presentation on strategies and challenges for the next generation of therapeutic antibodies.³ By analyzing the regulatory approvals of IgG-based biotherapeutic agents in the past ten years, we can gain insights into the successful strategies used by pharmaceutical companies so far to bring innovative drugs to the market. Strategies to optimize the structure of IgG antibodies and to design related or new structures with additional functions were presented. A detailed knowledge of antibody structure and activity now allows researchers to engineer primary antibodies on a more rational basis. Most approved antibodies are chimeric, humanized or human IgGs with similar constant domains. Numerous studies looking at the structure-function relationships of these antibodies have been published in the past five years with the aim of identifying antibody microvariants⁴ and investigating the influence of these variants on antigen binding, stability, pharmacokinetics (PK) and pharmacodynamics (PD). This knowledge is now being used to increase homogeneity and mitigate the chemistry, manufacture and control (CMC) liabilities of preclinical antibody candidates by genetic engineering. The removal by mutation of instability or aggregation hot spots in the antibody complementarity-determining regions (CDRs), and the use of hinge-stabilized or aglycosylated IgG4, are just a few examples of antibodies with improved pharmacological properties, including decreased heterogeneity, that are currently in development.Dr. Beck explained that the variable fragment (Fv) of an antibody is responsible for interactions with antigens and dictates essential properties such as binding affinity and target specificity. The origin of the Fv in therapeutic antibodies can be diverse, e.g., hybridomas, human antibody libraries, rodents with a human antibody repertoire or primatized or humanized antibodies from various species. Affinity maturation allows the binding affinity of the Fv to be improved or target selectivity to be modulated. The constant fragment (Fc) of an antibody is responsible for interactions with immune cells, and the associated properties of the Fc can also be modulated by engineering at several levels:⁵ altering the glycosylation status to regulate anti- and pro-inflammatory properties, modulating antibody-dependent cellular cytotoxicity (ADCC) by site-directed mutagenesis to alter binding to Fc receptors, increasing the serum half-life by Fc engineering to increase binding to the neonatal Fc receptor (FcRn), thereby preventing IgG degradation, and increasing complement activation by isotype chimerism. Additional functions can be endowed on antibodies by conjugation to other drugs. To date, the clinical success of antibody-drug conjugates (ADCs) has been limited. Nevertheless, promising new ADCs that include linkers with optimized properties (e.g., hydrolysable in the cytoplasm, resistant or susceptible to proteases or resistant to multi-drug resistance efflux pumps) and highly cytotoxic drugs are being studied in advanced clinical trials (e.g., trastuzumab emtansine, inotuzumab ozogamicin and brentuximab vedotin).⁶ IgGs have also been engineered to contain unique drug conjugation positions to obtain uniform and more homogeneous drug conjugates, such as ThioMab-drug conjugates, which have a uniform stoichiometry of approximately two coupled drugs per antibody molecule. Collectively, these advances should open new therapeutic avenues to deliver highly cytotoxic drugs with increased tolerability.     

Antibody–drug conjugates (ADCs) for cancer therapy: Strategies,challenges, and successes

Targeted delivery of therapeutic molecules into cancer cells is considered as a promising strategy to tackle cancer. Antibody–drug conjugates (ADCs), in which a monoclonal antibody (mAb) is conjugated to biologically active drugs through chemical linkers, have emerged as a promising class of anticancer treatment agents, being one of the fastest growing fields in cancer therapy. The failure of early ADCs led researchers to explore strategies to develop more effective and improved ADCs with lower levels of unconjugated mAbs and more-stable linkers between the drug and the antibody, which show improved pharmacokinetic properties, therapeutic indexes, and safety profiles. Such improvements resulted in the US Food and Drug Administration approvals of brentuximab vedotin, trastuzumab emtansine, and, more recently, inotuzumab ozogamicin. In addition, recent clinical outcomes have sparked additional interest, which leads to the dramatically increased number of ADCs in clinical development. The present review explores ADCs, their main characteristics, and new research developments, as well as discusses strategies for the selection of the most appropriate target antigens, mAbs, cytotoxic drugs, linkers, and conjugation chemistries.     

World Antibody Drug Conjugate Summit Europe: February 21–23, 2011; Frankfurt,Germany

The World Antibody Drug Conjugate Summit Europe, organized by Biorbis/Hanson Wade was held in Frankfurt, Germany February 21–23, 2011. Antibody drug conjugates (ADCs), also called immunoconjugates, are becoming an increasingly important class of therapeutics as demonstrated by the attendance of nearly 100 delegates at this highly focused meeting. Updates on three ADCs that are in late-stage clinical development, trastuzumab emtansine (T-DM1), brentuximab vedotin (SGN-35) and inotuzumab ozogamicin (CMC-544), were presented by speakers from ImmunoGen, Genentech, Roche, Seattle Genetics and Pfizer. These ADCs have shown encouraging therapeutic effects against solid tumors (T-DM1) and hematological malignancies (SGN-35, CMC-544). The key feature of the new generation of ADCs is the effective combination of the cytotoxicity of natural or synthetic highly potent antineoplastic agents, tumor selective monoclonal antibodies and blood-stable optimized linkers. Early clinical data for ADCs were showcased by Progenics Pharmaceuticals (PSMA ADC), Celldex (CDX-011) and Biotest (BT-062). Takeda, MedImmune and sanofi-aventis outlined their strategies for process development and analytical characterization. In addition, presentations on duocarmycin based-ADCs, α emitting immunoconjugates and antibody-conjugated nanoparticles were given by representatives from Syntarga, Algeta and the University of Stuttgart, respectively.Key words: antibody drug conjugates, immunoconjugates, trastuzumab emtansine, brentuximab vedotin, inotuzumab ozogamicin, oncology, cancer     

First-In-Human,Phase 1, Randomized,Dose-Escalation Trial with Recombinant Anti–IL-20 Monoclonal Antibody in Patients with Psoriasis

Background

The current trial was a first-in-human clinical trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the recombinant monoclonal anti−interleukin-20 (IL-20) antibody, NNC0109-0012, which targets the inflammatory cytokine IL-20.

Methods

In total, 48 patients aged 18 to 75 years with moderate to severe stable chronic plaque psoriasis with affected body surface area ≥15% and physician global assessment score ≥3 were enrolled in this randomized, double-blind, multicenter, placebo-controlled, phase 1 dose-escalation trial. Patients were randomized within each single dose cohort (0.01, 0.05, 0.2, 0.6, 1.5, or 3.0 mg/kg) or multiple dose cohort (0.05, 0.2, 0.5, 1.0, or 2.0 mg/kg; 1 dose every other week for 7 weeks) of NNC0109-0012 or placebo in a 3:1 ratio. In the expansion phase, 7 patients were randomized to weekly doses of 2.0 mg/kg NNC0109-0012 or placebo for 7 weeks. The primary objective, safety and tolerability, was assessed by evaluating adverse events (AEs). Additional endpoints included pharmacokinetics, pharmacodynamics, and clinical response (assessed using the Psoriasis Area and Severity Index [PASI] score).

Results

AEs were reported in 85% of patients (n = 40) in the initial study phases (NNC0109-0012, 83%; placebo, 92%) and in 4 of 7 patients in the multiple-dose expansion phase. One serious AE was reported but was judged not to be causally related to NNC0109-0012. No dose-limiting toxicities were reported. NNC0109-0012 pharmacokinetics was similar to other monoclonal antibodies, with an average half-life of approximately 3 weeks. There was a dose-proportional increase in area under the curve and maximum concentration after single dosing. No substantial changes in pharmacodynamic parameters were observed. The expansion phase was terminated early due to apparent lack of PASI improvement.

Conclusion

Single and multiple doses of NNC0109-0012, ranging from 0.05 to 3.0 mg/kg, were well tolerated in patients with psoriasis and exhibited pharmacokinetics similar to that of other monoclonal antibodies.

Trial Registration

ClinicalTrials.gov NCT01261767     

BiHC,a T-Cell–Engaging Bispecific Recombinant Antibody,Has Potent Cytotoxic Activity Against Her2 Tumor Cells

Among different cancer immunotherapy approaches, bispecific antibodies (BsAbs) are of great interest due to their ability to recruit immune cells to kill tumor cells directly. Various BsAbs against Her2 tumor cells have been proposed with potent cytotoxic activities. However, most of these formats require extensive processing to obtain heterodimeric bispecific antibodies. In this study, we describe a bispecific antibody, BiHC (bispecific Her2-CD3 antibody), constructed with a single-domain anti-Her2 and a single-chain Fv (variable fragment) of anti-CD3 in an IgG-like format. In contrast to most IgG-like BsAbs, the two arms in BiHC have different molecular weights, making it easier to separate hetero- or homodimers. BiHC can be expressed in Escherichia coli and purified via Protein A affinity chromatography. The purified BiHC can recruit T cells and induce specific cytotoxicity of Her2-expressing tumor cells in vitro. The BiHC can also efficiently inhibit the tumor growth in vivo. Thus, BiHC is a promising candidate for the treatment of Her2-positive cancers.     

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.     

Antibody humanization methods – a review and update

This article reviews recent advances achieved during recent years on various aspects of antibody humanization theories and techniques. Common methods for producing humanized antibodies including framework-homology-based humanization, germline humanization, complementary determining regions (CDR)-homology-based humanization and specificity determining residues (SDR) grafting, as well as advantages and disadvantages of each of these methods and their applications are discussed.     

Antibody–drug conjugates as novel anti-cancer chemotherapeutics

Over the past couple of decades, antibody–drug conjugates (ADCs) have revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumour-associated target antigens and deliver a highly potent cytotoxic agent. The synergistic combination of mAbs conjugated to small-molecule chemotherapeutics, via a stable linker, has given rise to an extremely efficacious class of anti-cancer drugs with an already large and rapidly growing clinical pipeline. The primary objective of this paper is to review current knowledge and latest developments in the field of ADCs. Upon intravenous administration, ADCs bind to their target antigens and are internalized through receptor-mediated endocytosis. This facilitates the subsequent release of the cytotoxin, which eventually leads to apoptotic cell death of the cancer cell. The three components of ADCs (mAb, linker and cytotoxin) affect the efficacy and toxicity of the conjugate. Optimizing each one, while enhancing the functionality of the ADC as a whole, has been one of the major considerations of ADC design and development. In addition to these, the choice of clinically relevant targets and the position and number of linkages have also been the key determinants of ADC efficacy. The only marketed ADCs, brentuximab vedotin and trastuzumab emtansine (T-DM1), have demonstrated their use against both haematological and solid malignancies respectively. The success of future ADCs relies on improving target selection, increasing cytotoxin potency, developing innovative linkers and overcoming drug resistance. As more research is conducted to tackle these issues, ADCs are likely to become part of the future of targeted cancer therapeutics.