Monoclonal Antibody Therapeutics History And Future-Books Pdf

Monoclonal antibody therapeutics history and future
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616 New technologies,Glossary Figure 1, IgG isotypes there are four IgG isotypes IgG1 IgG2 IgG3 and. IgG4 each with structurally and or functionally distinct constant. domains From a mAb drug development perspective IgG1 is often. the preferred isotype due to its ability to elicit effector function and. high intrinsic stability If effector function is not desirable IgG2 and VH. IgG4 have strongly reduced effector function however both of these. are associated with intrinsic stability issues IgG3 exhibits similar VL CH1 CDR. effector function to IgG1 but is rarely used in drug development due to. its short serum half life intrinsic instability and allotypic. polymorphisms Fab CL, Effector function the ability of an antibody to trigger cell lysis either. through engagement of activating Fcg receptor on effector cells. referred to as antibody dependent cytotoxicity ADCC or by fixing. complement and activation of the complement cascade. complement dependent cytotoxicity CDC, Phage display laboratory technique for the study of protein protein. or protein peptide interactions that uses bacteriophages to connect. proteins with the genetic information that encodes them Phage. display of antibody fragments has been exploited for the in vitro. isolation of therapeutic antibodies, Anti drug antibodies ADAs the immune system can develop an. antibody response to protein drugs including mAbs which are Current Opinion in Pharmacology. referred to as anti drug antibodies ADAs may cause or contribute to. drug induced hypersensitivity and serum sickness and can alter the. pharmacokinetic profile and reduce the efficacy of a protein drug Antibody structure Immunoglobulin G IgG Abs are large approximately. Anaphylatoxins small pro inflammatory polypeptides that are 150 kDa proteins comprising pairs of heavy and light chains connected. produced during activation of the complement system and by disulphide bonds The heavy chains contain a variable domain VH a. consequent cleavage of complement factor C3 C4 or C5 This results hinge region and three constant CH1 CH2 and CH3 domains The light. in the generation of anaphylatoxins C3a C4a and C5a of the C3 and chains contain one variable VL and one constant CL domain IgG. C5 convertase and membrane attack complex structure can also be divided into the Fragment antigen binding Fab. Antibody glycosylation an enzymatic post translational region that is composed of one constant and one variable domain of. modification process that results in the attachment of glycans to both the light VL and CL and the heavy VH and CH1 chain and the. antibody heavy chains Antibody glycosylation typically affects Ab fragment crystallizable Fc domain that is composed of two constant. effector function and half life domains CH2 and CH3 The specificity of Abs is mediated by their. Half life or elimination half life in pharmacokinetics this is the time variable domains and represented by the Fab region The variable. required for the plasma serum concentration of a drug to decrease by domains can be further subdivided into hypervariable regions or. half its steady state concentration complementarity determining regions CDR which bind to the antigen. directly and framework regions which serve as a scaffold for the CDR to. contact the antigen, more directed lead isolation and control over the specificity.
and affinity of the mAb 18 They should therefore be mAbs with other isotypes showing much reduced effector. considered as complementary technologies that have made function 20 ADCC is triggered by the Ab through. therapeutic mAbs more accessible than ever before with engagement of Fcg receptors FcgRs expressed on. approximately 30 mAbs being marketed in the US and or immune effector cells eventually resulting in killing of. Europe Table 1 and a record number of mAbs in clinical the target cell CDC is triggered by C1q binding to an Ab. development 19 which leads to release of anaphylatoxins the formation of. the membrane attack complex activation of C1q recep. For this review four key areas in mAb research were tors on effector cells and ultimately death of the target. identified that have either seen substantial recent advance cell Depending on the therapeutic goal triggering effec. ment or are anticipated to represent areas of significant tor function can either be desirable or undesirable. advancement and application going forward These are Fc. engineering Ab drug conjugates bispecifics and brain The amino acid residues in the Fc domain and Ab hinge. delivery of mAbs all of which are briefly discussed below region that interact with FcgRs C1q and FcRn have been. identified 21 In addition it is known that glycosylation. Optimizing monoclonal antibodies Fc of the Fc domain impacts on effector function 22 All of. engineering these offer opportunities for Fc engineering and mAb. Whilst the variable regions broadly determine the speci optimization Mutation of key amino acid residues and. ficity and selectivity of a mAb the Fc region adds con techniques to modify glycosylation of the Fc domain have. siderable functionality to the molecule The Fc region been employed to either increase or decrease binding of. can interact with the FcRn thus mediating an extended therapeutic mAbs to FcgRs or C1q thereby modulating. half life Figure 2 and dependent on isotype by med effector function without impacting binding to FcRn. iating effector function ADCC and or CDC ADCC and These modifications have been extensively reviewed. CDC are predominantly triggered by IgG1 and IgG3 elsewhere 23 24. Current Opinion in Pharmacology 2012 12 615 622 www sciencedirect com. Monoclonal antibody therapeutics history and future Buss et al 617. Circulating Circulating,IgG Serum IgG,pH 7 0 7 4,Uptake into. endosome IgG is,pH 6 0 6 5 released,Recycling of,pH dependent. Unbound IgG is,degraded in,Endothelial lysosome,Current Opinion in Pharmacology. Antibody recycling via the neonatal fc receptor FcRn The long half life of Abs is the consequence of Ab salvage from the lysosomal pathway by FcRn as. originally proposed by Brambell et al in 1964 58 The Fc region binds to FcRn in endosomes pH 6 0 6 5 and is diverted away from the degradative. lysosomal pathway Recycled IgG is released at the cell surface and this interaction with the FcRn is responsible for the long half life of Abs. In addition to modulation of effector function Fc engin Finally Fc engineering can be employed to stabilize. eering has been employed to further extend mAb half life IgG molecules The most striking example is with the. For example a twofold to fourfold improvement of the half IgG4 isotype which is infrequently used for thera. life for IgG1 mAbs has been achieved by introducing peutic mAbs as IgG4s can undergo half Ab formation. mutations that increase binding to FcRn under acidic due to Fab arm exchange with endogenous IgG4. endosomal pH conditions allowing for less frequent dosing 30 31 This may impact on mAb pharmacokinetics. 25 27 Furthermore whilst IgG3s mediate both ADCC result in monovalency and affect the avidity and. and CDC they exhibit a short half life and are therefore not activity of the mAb However it has been shown that. considered a suitable isotype for therapeutic mAbs 28 mutations in the hinge region of IgG4 mAbs stabilize. However it has recently been shown that replacing argi the molecule and reduce Fab arm exchange which may. nine at position 435 a key contact residue with FcRn with increase the therapeutic use of this IgG subclass. a histidine results in improved binding of IgG3 to FcRn 32 33 Thus Fc engineering has opened up opportu. under acidic pH conditions and a serum half life that is nities for creating a much wider range of differentiated. comparable to that of an IgG1 molecule 29 This opens mAb based molecules whose activity can be tailored to. up the possibility of engineering therapeutic IgG3 mAbs specific therapeutic indications. www sciencedirect com Current Opinion in Pharmacology 2012 12 615 622. 618 New technologies, Figure 3 or lysosomes 37 and the lack of differentiating efficacy. with this ADC is possibly linked to a lack of in vivo linker. stability In contrast brentuximab vedotin has a dipeptide. linker that is cleaved by lysosomal enzymes after intern. alization and is highly stable in vivo 38,More recently amide bond based linkers have been.
developed that remain attached covalently to the cyto. toxin after lysosomal degradation of the mAb 39, Furthermore Shen et al have shown that the site of. conjugation of the reactive cysteine thiol group in the. Murine Chimeric, mAb used for coupling maleimide linkers can differen. tially influence the stability efficacy and safety of the. ADC depending on accessibility to reactive thiols in. albumin free cysteine or glutathione in plasma 40, Optimization of the ratio of cytotoxin molecules per mAb. is another key consideration for ADC design A three to. four payload mAb ratio is considered optimal with higher. ratios being associated with ADC aggregation loss of. affinity for the target and rapid systemic clearance which. is exacerbated if the drug and linker are hydrophobic 41. Humanized Human, zumab umab The relatively limited success of mAb monotherapy in. oncology has fuelled interest in ADCs and it is likely that. this molecule class will only gain further interest in. Current Opinion in Pharmacology pharmaceutical development in the years ahead. Monoclonal antibody types and nomenclature Therapeutic mAbs can Bispecifics. be murine suffix omab chimeric suffix ximab humanized suffix Bispecifics comprise a diverse group of mAb based thera. e g zumab or human e g umab and are named accordingly peutics that can have multiple functionally different. binding domains within the same construct that allow. for interaction with two target antigens These should not. Antibody drug conjugates be confused with mAb mixtures which have recently. The ideal antibody drug conjugate ADC combines a emerged as a novel and exciting way to target multiple. mAb with specificity for typically a tumour specific antigens or multiple epitopes within the same antigen. antigen with no or low expression in normal tissues with 42 Bispecifics can exist in many different formats. a highly potent cytotoxic chemical The cytototoxic from tandem monovalent binding fragments to IgG. chemical is attached to the mAb using a linker that based Abs onto which multiple additional antigen bind. maintains stability in the systemic circulation yet enables ing domains are attached 43 44 24 Full length anti. release of the cytotoxin when the mAb is bound to or is body structures offer advantages over fragment based. internalized by a target cancer cell Thus far only two formats because they benefit from the pharmacokinetic. ADCs have been approved for use in humans with one of properties and potentially effector function of the Fc. these gemtuzumab ozogamicin MylotargTM being domain. voluntarily withdrawn as its efficacy did not differentiate. from chemotherapy alone 34 Nevertheless the recent The first bispecific to reach the market in 2009 was. approval of brentuximab vedotin AdcetrisTM 35 and catumaxomab RemovabTM for the treatment of malig. the therapeutic potential of trastuzumab emantisine T nant ascites in patients with human epithelial cell. DM1 microtubule polymerization inhibitor mertansine adhesion molecule EpCAM positive carcinoma This. conjugated to trastuzumab 36 has signalled a new era in rat mouse hybrid IgG2a b bispecific simultaneously tar. the interest and development of ADCs gets CD3 on T cells and EpCAM on tumour cells to. facilitate killing of tumour cells and could be considered a. The synthetic linkers used for conjugation are generally trifunctional molecule as the Fc region creates a third. either cleavable disulphide based hydrazone or peptide functional binding site to facilitate ADCC 45 Currently. linkers or non cleavable e g non reducible thioether many bispecifics in development tend to work to similar. bond and can impact significantly on the efficacy of the principles of catumaxomab and aim to bring effector cells. ADC Gemtuzumab ozogamicin contains an acid labile into close contact with specific tumour associated anti. hydrazone linker that is hydrolyzed in acidic endosomes gens to facilitate cell killing a strategy that was first. Current Opinion in Pharmacology 2012 12 615 622 www sciencedirect com. Monoclonal antibody therapeutics history and future Buss et al 619. Licensed therapeutic mAbs, Scientific name Trade name Origin and isotype Target Licensed indication s and year of.
first approval region, Capromab pendetide Prostascint Murine IgG1 PSA a Diagnostic imaging 1996 US. Muronomab CD3 Orthoclone Murine IgG2a CD3 Transplant rejection 1992 US. Tositumumab iodine 131 Bexxar Murine IgG2 CD20 NHLb 2003 US. Ibritumomab tiuxetan Zevalin Murine IgG1 CD23 NHL 2002 US 2004 EU. Basiliximab Simulect Chimeric IgG1 CD25 Prophylaxis for transplant rejection 1998 US. Brentuximab vedotin Adcetris Chimeric IgG1 CD30 ADC c ALCLd and Hodgkin lymphoma 2011 US. Catumaxomab Removab Chimeric IgG2a b CD3 EpCAM e Malignant ascites 2009 EU. Cetuximab Erbitux Chimeric IgG1 EGFR f Colorectal head and neck cancer 2004 US EU. Infliximab Remicade Chimeric IgG1 TNF g RAh ankylosing spondylitis Crohn s disease. ulcerative colitis 1998 US 1999 EU, Rituximab Rituxan Chimeric IgG1 CD20 B cell non Hodgkin lymphoma 1997 US 1998 EU. Alemtuzumab Campath Humanized IgG1 CD52 B CLLi 2001 US. MabCampath, Bevacizumab Avastin Humanized IgG1 VEGF j Colorectal lung breast cancer 2004 US 2005 EU. Daclizumab Zenapax Humanized IgG1 CD25 Prophylaxis for transplant rejection 1997 US. 1999 EU withdrawn 2009, Eculizumab Soliris Humanized IgG2 4 Complement Paroxysmal nocturnal haemoglobinuria atypical. factor 5 haemolytic uremic syndrome 2007 US, Efalizumab Raptiva Humanized IgG1 CD11a Psoriasis 2003 US withdrawn 2009.
Gentuzumab ozogamcin Mylotarg Humanized IgG4 CD33 ADC Leukemia 2000 US. Natalizumab Tysabri Humanized IgG4 a4b1 integrin Multiple sclerosis 2004 US 2006 EU. Omalizumab Xolair Humanized IgG1 IgE Severe asthma 2003 US 2005 EU. Palivizumab Synagis Humanized IgG1 RSVk F protein Prevention of RSV infection in neonates 1998 US. Ranibizumab Lucentis Humanized IgG1 VEGF Macular degeneration 2006 US 2007 EU. Tocilizumab Actemra Humanized IgG1 IL 6R l Castleman s syndrome RA 2010 US 2009 EU. Trastuzumab Herceptin Humanized IgG1 HER 2 m HER 2 positive breast cancer 1998 US. Adalimumab Humira Human IgG1 TNF RA Crohn s disease plaque psoriasis 2002 US. Belimumab Benlysta Human IgG1 BLys n Systemic lupus erythematosus. Canakinumab Ilaris Human IgG1 IL 1b o Muckle Wells syndrome US EU 2009. Denosumab Prolia Xgeva Human IgG2 RANKL p Osteoporosis bone metastasis 2009 US EU. Golimumab Simponi Human IgG1 TNF RA psoriatic arthritis ankylosing spondylitis. 2009 US EU, Ipilimumab Yervoy Human IgG1 CTLA4 q Advanced melanoma 2011 US EU. Ofatumumab Arzerra Human IgG1 CD20 CLL 2009 US 2010 EU. Panitumumab Vectibix Human IgG2 EGFR Colorectal cancer 2007 US EU. Ustekinumab Stelara Human IgG1 IL 12p40 r Plaque psoriasis 2009 US EU. Pertuzumab Perjeta Humanized IgG1 HER 2 m HER 2 positive breast cancer 2012 US. PSA prostate antigen,NHL non Hodgkin lymphoma,ADC antibody drug conjugate. ALCL anaplastic large cell lymphoma,EpCAM epithelial cell adhesion molecule. EGFR epidermal growth factor receptor,TNF tumour necrosis factor. RA rheumatoid arthritis,B CLL B cell chronic lymphocytic leukemia.
VEGF vascular endothelial growth factor,RSV respiratory syncytial virus. IL 6R interleukin 6 receptor,HER 2 human epidermal growth factor receptor 2. BLys B lymphocyte stimulator,IL 1b interleukin 1b, RANKL receptor activator of nuclear factor kappa B ligand. CTLA4 cytotoxic T lymphocyte antigen 4, IL 12p40 interleukin 12 p40 subunit CD cluster of differentiation. www sciencedirect com Current Opinion in Pharmacology 2012 12 615 622. 620 New technologies, suggested in the 1980s 46 47 The promise of immune stability In addition much more complex mAb based.
cell re targeting and synergistic enhanced efficacy therapies such as ADCs bispecifics mAb mixtures and. through engagement of multiple targets gives bispecifics potentially brain penetrant mAbs are being developed. the potential to revolutionize Ab therapy in the next These novel mAb based therapeutics will likely revolu. decade tionize drug therapy in a wide spectrum of disease areas. and will hopefully be able to address significant unmet. Targeting and delivery of mAbs to the brain medical needs. With respect to neuro oncology and neurodegenerative. disorders one of the major disadvantages of therapeutic References and recommended reading. mAbs is their inability to cross the blood brain barrier Papers of particular interest published within the period of review. have been highlighted as,BBB In mice less than 1 of a systemically adminis. tered mAb is detected in the brain 48 whilst in man of special interest. of outstanding interest, cerebrospinal fluid CSF levels have been observed to be. 300 times lower than in serum 49 50 However for 1 Kohler G Milstein C Continuous cultures of fused cells. targeting diseases of the brain increased brain penetra secreting antibody of predefined specificity Nature 1975. tion could be highly beneficial Many approaches for 256 495 497. delivering mAbs in the brain have been investigated 2 Ober RJ Radu CG Ghetie V Ward ES Differences in. promiscuity for antibody FcRn interactions across species. from intracranial injection of mAbs to disruption of the implications for therapeutic antibodies Int Immunol 2001. BBB 51 In addition alternative routes of delivery to the 13 1551 1559. brain such as intranasal intrathecal or intraventricular 3 Stern M Herrmann R Overview of monoclonal antibodies in. delivery have been explored 52 However all of these cancer therapy present and promise Crit Rev Oncol Hematol. 2005 54 11 29, approaches have significant practical issues Newer less. tried and tested delivery systems such as liposomes 4 Morrison SL Johnson MJ Herzenberg LA Oi VT Chimeric. human antibody molecules mouse antigen binding domains. microspheres nanoparticles nanogels microchips biode with human constant region domains Proc Natl Acad Sci USA. gradeable polymers and bionanocapsules are also under 1984 81 6851 6855. investigation 53 5 Presta LG Engineering of therapeutic antibodies to minimize. immunogenicity and optimize function Adv Drug Deliv Rev. 2006 58 640 656,Recent interest has shifted to Trojan horse like. approaches involving bispecific mAbs that bind to recep 6 Jones PT Dear PH Foote J Neuberger MS Winter G Replacing. the complementarity determining regions in a human. tors located on the endothelial cells of the BBB to antibody with those from a mouse Nature 1986 321 522 525. facilitate receptor mediated transcytosis of the other 7 McCafferty J Griffiths AD Winter G Chiswell DJ Phage. arm of the bispecific into the brain Yu et al recently antibodies filamentous phage displaying antibody variable. domains Nature 1990 348 552 554, reported delivery of a bispecific anti transferrin receptor The seminal paper describing how single chain Fv Ab phage display.
anti beta secretase BACE1 construct which showed technology can be used to create a library of Ab genes that has subse. good brain exposure in the rat compared to the anti quently been used and modified by others to build large human Ab. libraries for therapeutic mAb generation and still forms the basis of the. BACE1 mAb alone 54 Alternatively a mAb for the technology used for therapeutic mAbs today. human insulin receptor which mediates transfer of 8 Winter G Griffiths AD Hawkins RE Hoogenboom HR Making. endogenous insulin through the BBB could also be used antibodies by phage display technology Annu Rev Immunol. 55 Another exciting approach involves the utilization of 1994 12 433 455. the camelid single domain Ab FC5 which appears to be 9 Vaughan TJ Williams AJ Pritchard K Osbourn JK Pope AR. Earnshaw JC McCafferty J Hodits RA Wilton J Johnson KS. able to cross the BBB in vitro and in vivo by binding to an Human antibodies with sub nanomolar affinities isolated from. unidentified luminal alpha 2 3 sialoglycoprotein recep a large non immunized phage display library Nat Biotechnol. 1996 14 309 314, tor which triggers clathrin mediated endocytosis 56 57. These exciting approaches may in the future allow for 10 Vaughan TJ Osbourn JK Tempest PR Human antibodies by. design Nat Biotechnol 1998 16 535 539, the delivery of mAbs and other biologics into the brain. This would offer new hope for effective therapies target 11 Hoet RM Cohen EH Kent RB Rookey K Schoonbroodt S. Hogan S Rem L Frans N Daukandt M Pieters H et al, ing neurological diseases with high unmet medical need Generation of high affinity human antibodies by combining. such as Alzheimer s multiple sclerosis and brain tumours donor derived and synthetic complementarity determining. region diversity Nat Biotechnol 2005 23 344 348, Conclusions 12 Jostock T Vanhove M Brepoels E Van Gool R Daukandt M. Wehnert A Van Hegelsom R Dransfield D Sexton D Devlin M. From the regulatory approval of the first murine mAb for et al Rapid generation of functional human IgG antibodies. therapeutic use in man in 1986 to the first bispecific mAb derived from Fab on phage display libraries J Immunol. Methods 2004 289 65 80, in 2009 mAbs and their derivatives are now key drug.
modalities in the pharmaceutical industry Advances in 13 Boulianne GL Hozumi N Shulman MJ Production of functional. chimaeric mouse human antibody Nature 1984 312 643 646. Ab engineering and mAb production techniques have, 14 Lonberg N Taylor LD Harding FA Trounstine M Higgins KM. enabled the clinical development of mAbs with tailored Schramm SR Kuo CC Mashayekh R Wymore K McCabe JG. properties with respect to half life effector function and et al Antigen specific human antibodies from mice. Current Opinion in Pharmacology 2012 12 615 622 www sciencedirect com. Monoclonal antibody therapeutics history and future Buss et al 621. comprising four distinct genetic modifications Nature 1994 Fab arm exchange with endogenous human IgG4 in vivo Nat. 368 856 859 Biotechnol 2009 27 767 771, 15 Green LL Hardy MC Maynard Currie CE Tsuda H Louie DM 32 Bloom JW Madanat MS Marriott D Wong T Chan SY Intrachain. Mendez MJ Abderrahim H Noguchi M Smith DH Zeng Y et al disulfide bond in the core hinge region of human IgG4 Protein. Antigen specific human monoclonal antibodies from mice Sci 1997 6 407 415. engineered with human Ig heavy and light chain YACs Nat. Genet 1994 7 13 21 33 Lu Y Harding SE Rowe AJ Davis KG Fish B Varley P Gee C. Mulot S The effect of a point mutation on the stability of IgG4. 16 Baker MP Reynolds HM Lumicisi B Bryson CJ Immunogenicity as monitored by analytical ultracentrifugation J Pharm Sci. of protein therapeutics the key causes consequences and 2008 97 960 969. challenges Self Nonself 2010 1 314 322, This review shows examples of what tools are available for reducing 34 Webb S Pharma interest surges in antibody drug conjugates. immunogenicity at an early stage before clinical development that could Nat Biotechnol 2011 29 297 298. aid in deselection of mAbs with high immunogenic potential or removal of. potential T cell epitopes 35 DeFrancesco L Seattle genetics rare cancer drug sails through. accelerated approval Nat Biotechnol 2011 29 851 852. 17 De Groot AS McMurry J Moise L Prediction of, immunogenicity in silico paradigms ex vivo and in vivo 36 Junttila TT Li G Parsons K Phillips GL Sliwkowski MX. correlates Curr Opin Pharmacol 2008 8 620 626 Trastuzumab DM1 T DM1 retains all the mechanisms of. action of trastuzumab and efficiently inhibits growth of. 18 Lonberg N Fully human antibodies from transgenic mouse and lapatinib insensitive breast cancer Breast Cancer Res Treat. phage display platforms Curr Opin Immunol 2008 20 450 459 2011 128 347 356. 19 Nelson AL Dhimolea E Reichert JM Development trends for 37 Hamann PR Hinman LM Hollander I Beyer CF Lindh D. human monoclonal antibody therapeutics Nat Rev Drug Discov Holcomb R Hallett W Tsou HR Upeslacis J Shochat D et al. 2010 9 767 774 Gemtuzumab ozogamicin a potent and selective anti CD33. antibody calicheamicin conjugate for treatment of acute. 20 Natsume A In M Takamura H Nakagawa T Shimizu Y Kitajima K myeloid leukemia Bioconjug Chem 2002 13 47 58. Wakitani M Ohta S Satoh M Shitara K et al Engineered. antibodies of IgG1 IgG3 mixed isotype with enhanced 38 Sanderson RJ Hering MA James SF Sun MM Doronina SO. cytotoxic activities Cancer Res 2008 68 3863 3872 Siadak AW Senter PD Wahl AF In vivo drug linker stability of. an anti CD30 dipeptide linked auristatin immunoconjugate. 21 An Z Forrest G Moore R Cukan M Haytko P Huang L Vitelli S Clin Cancer Res 2005 11 843 852. Zhao JZ Lu P Hua J et al IgG2m4 an engineered antibody. isotype with reduced Fc function MAbs 2009 1 572 579 39 Alley SC Benjamin DR Jeffrey SC Okeley NM Meyer DL. Sanderson RJ Senter PD Contribution of linker stability to the. 22 Abe s R Teillaud JL Impact of glycosylation on effector activities of anticancer immunoconjugates Bioconjug Chem. functions of therapeutic IgG Pharmaceuticals 2010 3 146 157 2008 19 759 765. 23 Strohl WR Optimization of Fc mediated effector functions of 40 Shen BQ Xu K Liu L Raab H Bhakta S Kenrick M Parsons. monoclonal antibodies Curr Opin Biotechnol 2009 20 685 691 Reponte KL Tien J Yu SF Mai E et al Conjugation site. modulates the in vivo stability and therapeutic activity of. 24 Chan AC Carter PJ Therapeutic antibodies for autoimmunity antibody drug conjugates Nat Biotechnol 2012 30 184 189. and inflammation Nat Rev Immunol 2010 10 301 316 Stability of an ADC for delivery of the cytotoxic chemical to the tumour is. A comprehensive review of how Ab engineering is being used to develop critical for therapeutic effectiveness and the authors show that the site of. next generation antibodies Whilst specifically relevant for autoimmunity conjugation of maleimido caproyl valine citruline p amino benzyloxy. and inflammation it explains core principles that apply to other thera carbonyl MC vc PAB linker with MMAE to three thio trastuzumab. peutic areas This reference comes from an edition of the journal that variants influences the in vivo stability efficacy and safety of an ADC. focuses on therapeutic antibodies which the authors encourage the. reader to refer to 41 Zhao RY Wilhelm SD Audette C Jones G Leece BA Lazar AC. Goldmacher VS Singh R Kovtun Y Widdison WC et al Synthesis. 25 Hinton PR Johlfs MG Xiong JM Hanestad K Ong KC Bullock C and evaluation of hydrophilic linkers for antibody. Keller S Tang MT Tso JY Va squez M et al Engineered human maytansinoid conjugates J Med Chem 2011 54 3606 3623. IgG antibodies with longer serum half lives in primates J Biol. Chem 2004 279 6213 6216 42 Pedersen MW Jacobsen HJ Koefoed K Hey A Pyke C. Haurum JS Kragh M Sym004 a novel synergistic anti, 26 Hinton PR Xiong JM Johlfs MG Tang MT Keller S Tsurushita N epidermal growth factor receptor antibody mixture with.
An engineered human IgG1 antibody with longer serum half superior anticancer efficacy Cancer Res 2010 70 588 597. life J Immunol 2006 176 346 356 The authors use a novel Ab mixture containing two mAbs directed. against distinct epitopes on the extracellular domain of EGFR that act. 27 Dall Acqua WF Kiener PA Wu H Properties of human IgG1s in a synergistic manner to show superior anti tumour efficacy in pre. engineered for enhanced binding to the neonatal Fc receptor clinical models compared to treatment with a single mAb. FcRn J Biol Chem 2006 281 23514 23524, 43 Mabry R Snavely M Therapeutic bispecific antibodies the. 28 Salfeld JG Isotype selection in antibody engineering Nat selection of stable single chain fragments to overcome. Biotechnol 2007 25 1369 1372 engineering obstacles IDrugs 2010 13 543 549. 29 Stapleton NM Andersen JT Stemerding AM Bjarnarson SP 44 Mu ller D Kontermann RE Bispecific antibodies for cancer. Verheul RC Gerritsen J Zhao Y Kleijer M Sandlie I de Haas M immunotherapy current perspectives BioDrugs 2010 24 89 98. et al Competition for FcRn mediated transport gives rise to. short half life of human IgG3 and offers therapeutic potential 45 Linke R Klein A Seimetz D Catumaxomab clinical. Nat Commun 2011 2 599 development and future directions MAbs 2010 2 129 136. Human IgG3 has substantial effector function but has a short half life. limiting its clinical potential However the authors show that by introdu 46 Staerz UD Kanagawa O Bevan MJ Hybrid antibodies can. cing an arginine to histidine mutation at position 435 R435H there is an target sites for attack by T cells Nature 1985 314 628 631. improved binding of IgG3 to FcRn and subsequent half life extension. comparable to IgG1 which may enable clinical use of an IgG3 therapeutic 47 Baeuerle PA Kufer P Bargou R BiTE teaching antibodies to. mAb eng age T cells for cancer therapy Curr Opin Mol Ther 2009. 30 Aalberse RC Schuurman J IgG4 breaking the rules Immunology Describes experimental evidence that both freshly isolated and in vitro. 2002 105 9 19 expanded human CD4 CD25 Tregs can be efficiently activated via. bispecific Abs in a target specific but TCR independent manner. 31 Labrijn AF Buijsse AO van den Bremer ET Verwilligen AY. Bleeker WK Thorpe SJ Killestein J Polman CH Aalberse RC 48 Banks WA Terrell B Farr SA Robinson SM Nonaka N Morley JE. Schuurman J et al Therapeutic IgG4 antibodies engage in Passage of amyloid beta protein antibody across the blood brain. www sciencedirect com Current Opinion in Pharmacology 2012 12 615 622. 622 New technologies, barrier in a mouse model of Alzheimer s disease Peptides 2002 of a therapeutic antibody by reducing its affinity for a. 23 2223 2226 transcytosis target Sci Transl Med 2011 3 84ra44. Demonstrated that a bispecific mAb one arm with low affinity to the BBB. 49 Pestalozzi BC Brignoli S Trastuzumab in CSF J Clin Oncol 2000 specific transferrin receptor and the other arm with a high affinity to anti. 18 2349 2351 BACE1 was more effective in reducing Ab peptide concentrations in the. mouse brain when compared to a monospecific anti BACE1 mAb. 50 Stemmler HJ Schmitt M Willems A Bernhard H Harbeck N. Heinemann V Ratio of trastuzumab levels in serum and 55 Boado RJ Lu JZ Hui EK Pardridge WM IgG single chain Fv. cerebrospinal fluid is altered in HER2 positive breast cancer fusion protein therapeutic for Alzheimer s disease expression. patients with brain metastases and impairment of blood brain in CHO cells and pharmacokinetics and brain delivery in the. barrier Anticancer Drugs 2007 18 23 28 rhesus monkey Biotechnol Bioeng 2010 105 627 635. 51 Frank RT Aboody KS Najbauer J Strategies for enhancing. 56 Abulrob A Sprong H Van Bergen en Henegouwen P Stanimirovic D. antibody delivery to the brain Biochim Biophys Acta 2011. The blood brain barrier transmigrating single domain antibody. 1816 191 198, mechanisms of transport and antigenic epitopes in human brain. 52 Patel MM Goyal BR Bhadada SV Bhatt JS Amin AF Getting into endothelial cells J Neurochem 2005 95 1201 1214. the brain approaches to enhance brain drug delivery CNS. Drugs 2009 23 35 58 57 Rutgers KS Nabuurs RJ van den Berg SA Schenk GJ Rotman M. Verrips CT van Duinen SG Maat Schieman ML van Buchem MA. 53 Silva GA Nanotechnology approaches to crossing the blood de Boer AG et al Transmigration of beta amyloid specific. brain barrier and drug delivery to the CNS BMC Neurosci 2008 heavy chain antibody fragments across the in vitro blood. 10 9 Suppl 3 S4 brain barrier Neuroscience 2011 190 37 42. 54 Yu YJ Zhang Y Kenrick M Hoyte K Luk W Lu Y Atwal J 58 Brambell FW Hemmings WA Morris IG A theoretical model of. Elliott JM Prabhu S Watts RJ Dennis MS Boosting brain uptake gamma globulin catabolism Nature 1964 203 1352 1354. Current Opinion in Pharmacology 2012 12 615 622 www sciencedirect com.

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E2 Framework - International Baccalaureate

E2 Framework International Baccalaureate

The IB Excellence and Equity (E2) initiative aims to support schools in their work to fully reflect their diversity and academic excellence by collaborating with public IB World Schools in the USA. This initiative challenges school leaders in the USA to consider how to elevate the conversation about what is academically possible for low-income and minority students. The focus goes beyond ...



the Pupil Deprivation Grant, building on its success in narrowing the attainment gap and breaking barriers to learning. The Health and Well-being AoLE will draw on subjects and themes from mental, physical and emotional well-being. All the AoLEs in the new arrangements will have parity, making metal health