Current progress in innovative engineered antibodies

Abstract

As of May 1, 2017, 74 antibody-based molecules have been approved by a regulatory authority in a major market. Additionally, there are 70 and 575 antibodybased molecules in phase III and phase I/II clinical trials, respectively. These total 719 antibody-based clinical stage molecules include 493 naked IgGs, 87 antibodydrug conjugates, 61 bispecific antibodies, 37 total Fc fusion proteins, 17 radioimmunoglobulins, 13 antibody fragments, and 11 immunocytokines. New uses for these antibodies are being discovered each year. For oncology, many of the exciting new approaches involve antibody modulation of T-cells. There are over 80 antibodies in clinical trials targeting T cell checkpoints, 26 T-cellredirected bispecific antibodies, and 145 chimeric antigen receptor (CAR) cell-based candidates (all currently in phase I or II clinical trials), totaling more than 250 T cell interacting clinical stage antibody-based candidates. Finally, significant progress has been made recently on routes of delivery, including delivery of proteins across the blood-brain barrier, oral delivery to the gut, delivery to the cellular cytosol, and gene- and viral-based delivery of antibodies. Thus, there are currently at least 864 antibody-based clinical stage molecules or cells, with incredible diversity in how they are constructed and what activities they impart. These are followed by a next wave of novel molecules, approaches, and new methods and routes of delivery, demonstrating that the field of antibody-based biologics is very innovative and diverse in its approaches to fulfill their promise to treat unmet medical needs.

Keywords

antibody clinical candidates / engineered antibodies / chimeric antigen receptors

References

[1] Abbott NJ, Patabendige AAK, Dolman DEM, Yusof SR, Begley DJ (2010) Structure and function of the blood-brain barrier. Neurobiol Dis 37:13–25

[2] Abulrob A, Sprong H, Henegouwen E, Van Bergen P, Stanimirovic D (2005) The blood–brain barrier transmigrating single domain antibody: mechanisms of transport and antigenic epitopes in human brain endothelial cells. J Neurochem 95:1201–1214

[3] Achkar T, Tarhini AA (2017) The use of immunotherapy in the treatment of melanoma. J Hematol Oncol 10:88.

[4] Adam VS, Crosariol M, Kumar S, Ge MO, Czack SE, Roy S, Haczku A, Tretiakova A, Wilson JM (2014) Adeno-associated virus 9-mediated airway expression of antibody protects old and immunodeficient mice against influenza virus. Clin Vaccine Immunol 21:1528–1533

[5] Adelfinger M, Bessler S, Frentzen A, Cecil A, Langbein-Laugwitz J, Gentschev I, Szalay AA (2015) Preclinical testing oncolytic vaccinia virus strain GLV-5b451 expressing an anti-VEGF singlechain antibody for canine cancer therapy. Viruses 7:4075–4092

[6] Alduaij W, Ivanov A, Honeychurch J, Cheadle EJ, Potluri S, Lim SH, Shimada K, Chan CHT, Tutt A, Beers SA (2011) Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies. Blood 117:4519–4528

[7] Anthony RM, Ravetch JV (2010) A novel role for the IgG Fc glycan: the anti-inflammatory activity of sialylated IgG Fcs. J Clin Immunol 30(Suppl 1):S9–14

[8] Antonia SJ, Vansteenkiste JF, Moon E (2016) Immunotherapy: beyond anti–PD-1 and anti–PD-L1 therapies. ASCO Educ Book 2016:e450–e458

[9] Baeuerle PA, Reinhardt C, Kufer P (2008) BiTE: a new class of antibodies that recruit T-cells. Drugs Future 33:137–147

[10] Baker K, Qiao S-W, Kuo T, Kobayashi K, Yoshida M, Lencer WI, Blumberg RS (2009) Immune and non- immune functions of the (not so) neonatal Fc receptor, FcRn. Semin Immunopathol 31:223–226

[11] Balazs AB, Ouyang Y, Hong CM, Chen J, Nguyen SM, Rao DS, An DS, Baltimore D (2014) Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission. Nat Med 20:296–300

[12] Barnhart BC, Quigley M (2017) The role of Fc-FcγR interactions in the anti-tumor activity of therapeutic antibodies. Immunol Cell Biol 95:340–346

[13] Beck A, Goetsch L, Dumontet C, Corvaïa N (2017) Strategies and challenges for the next generation of antibody–drug conjugates. Nat Rev Drug Discov 16:315–337

[14] Beerli RR, Hell T, Merkel AS, Grawunder U (2015) Sortase enzymemediated generation of site- specifically conjugated antibody drug conjugates with high in vitro and in vivo potency. PLoS ONE 10:e0131177.

[15] Bird RE, Hardman KD, Jacobson JW, Johnson S, Kaufman BM, Lee SM, Lee T, Pope SH, Riordan GS, Whitlow M (1988) Single-chain antigen-binding proteins. Science 242:423–426

[16] Bluemel C, Hausmann S, Fluhr P, Sriskandarajah M, Stallcup WB, Baeuerle PA, Kufer P (2010) Epitope distance to the target cell membrane and antigen size determine the potency of T cellmediated lysis by BiTE antibodies specific for a large melanoma surface antigen. Cancer Immunol Immunother 59:1197–1209

[17] Boado RJ, Pardridge WM (2017) Brain and organ uptake in the rhesus monkey in vivo of recombinant iduronidase compared to an insulin receptor antibody-iduronidase fusion protein. Mol Pharm 14:1271–1277

[18] Boado RJ, Zhang Y, Zhang Y, Pardridge WM (2007) Humanization of anti-human insulin receptor antibody for drug targeting across the human blood-brain barrier. Biotechnol Bioeng 96:381–391

[19] Boado RJ, Hui EK, Lu JZ, Pardridge WM (2012)Glycemic control and chronic dosing of rhesus monkeys with a fusion protein of iduronidase and a monoclonal antibody against the human insulin receptor. Drug Metab Dispos 40:2021–2025

[20] Boado RJ, Hui EK-W, Lu JZ, Pardridge WM (2014) Insulin receptor antibody-iduronate 2-sulfatase fusion protein: pharmacokinetics, anti-drug antibody, and safety pharmacology in rhesus monkeys. Biotechnol Bioeng 111:2317–2325

[21] Bolt S, Routledge E, Lloyd I, Chatenoud L, Pope H, Gorman SD, Clark M, Waldmann H (1993) The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties. Eur J Immunol 23:403–411

[22] Bommareddy PK, Patel A, Hossain S, Kaufman HL (2017) Talimogene laherparepvec (T-VEC) and other oncolytic viruses for the treatment of melanoma. Am J Clin Dermatol 18:1–15

[23] Borrok MJ, Mody N, Lu X, Kuhn M, Wu H, Dall’Acqu WF, Tsui P (2017) An ‘Fc silenced’ IgG1 format with extended half-life designed for improved stability. J Pharm Sci.

[24] Bossi G, Buisson S, Oates J, Jakobsen BK, Hassan NJ (2014) ImmTAC-redirected tumour cell killing induces and potentiates antigen cross-presentation by dendritic cells. Cancer Immunol Immunother 63:437–448

[25] Bostrom J, Yu S-F, Kan D, Appleton BA, Lee CV, Billeci K, Man W, Peale F, Ross S, Wiesmann C, Fuh G (2009) Variants of the antibody herceptin that interact with HER2 and VEGF at the antigen binding site. Science 323:1610–1614

[26] Brack S, Attinger-Toller I, Schade B, Mourlane F, Klupsch K, Woods R, Hachemi H, von der Bey U, Koenig- Friedrich S, Bertshinger J, Grabulovski D (2014) A bispecific HER2-targeting FynomAb with superior antitumor activity and novel mode of action. Mol Cancer Ther 13:2030–2039

[27] Brennan M, Davison PF, Paulus H (1985) Preparation of bispecific antibodies by chemical recombination of monoclonal immunoglobulin G1 fragments. Science 229:81–83

[28] Brezski RJ, Georgiou G (2016) Immunoglobulin isotype knowledge and application to Fc engineering. Curr Opin Immunol 40:62–69

[29] Brinkmann U, Kontermann RE (2017) The making of bispecific antibodies. mAbs 9:182–212

[30] Cancro MP, D’Cruz DP, Khamasta MA (2009) The role of B lymphocyte stimulator (BLyS) in systemic lupus erythematosus. J Clin Investig 119:1066–1073

[31] Capon DJ, Chamow SM, Mordenti J, Marsters SA, Gregory T, Mitsuya H, Byrn RA, Lucas C, Wurm FM, Groopman JE (1989) Designing CD4 immunoadhesins for AIDS therapy. Nature 337:525–531

[32] Carotta S (2016) Targeting NK cells for anticancer immunotherapy: clinical and preclinical approaches. Front Immunol 7:152.

[33] Carvalho S, Levi-Schaffer F, Sela M, Yarden Y (2016) Immunotherapy of cancer: from monoclonal to oligoclonal cocktails of anticancer antibodies: IUPHAR Review 18. Br J Pharmacol 173:1407–1424

[34] Chaparro-Riggers J, Liang H, DeVay RM, Bai L, Sutton JE, Chen W, Geng T, Lindquist K, Casas MG, Boustany LM (2012) Increasing serum half-life and extending cholesterol lowering in vivo by engineering antibody with pH-sensitive binding to PCSK9. J Biol Chem 287:11090–11097

[35] Chelius D, Ruf P, Gruber P, Plöscher M, Liedtke R, Gansberger E, Hess J, Wasiliu M, Lindhofer H (2010) Structural and functional characterization of the trifunctional antibody catumaxomab. mAbs 2:309–319

[36] Chikuma S, Kanamori M, Mise-Omata S, Yoshimura A (2017) Suppressors of cytokine signaling: potential immune checkpoint molecules for cancer immunotherapy. Cancer Sci 108:574–580

[37] Chmielewski M, Hombach AA, Abken H (2014) Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma. Immunol Rev 257:83–90

[38] Choi D-K, Bae J, Shin S-M, Shin J-Y, Kim S, Kim Y-S (2014) A general strategy for generating intact, full- length IgG antibodies that penetrate into the cytosol of living cells. mAbs 6:1402–1414

[39] Choy EH, Hazleman B, Smith M, Moss K, Lisi L, Scott DG, Patel J, Sopwith M, Isenberg DA (2002) Efficacy of a novel PEGylated humanized anti-TNF fragment (CDP870) in patients with rheumatoid arthritis: a phase II double-blinded, randomized, doseescalating trial. Rheumatol 41:1133–1137

[40] Chromikova V, Mader A, Hofbauer S, Göbl C, Madl T, Gach JS, Bauenfried S, Furtmüller PG, Forthal DN, Mach L (2015) Introduction of germline residues improves the stability of anti-HIV mAb 2G12- IgM. Biochim Biophys Acta 1854:1536–1544

[41] Clark RH, Latypov RF, De Imus C, Carter J, Wilson Z, Manchulenko K, Brown ME, Ketchem RR (2014) Remediating agitationinduced antibody aggregation by eradicating exposed hydrophobic motifs. mAbs 6:1540–1550

[42] Coloma MJ, Morrison SL (1997) Design and production of novel tetravalent bispecific antibodies. Nat Biotechnol 15:159–163

[43] Cook EM, Lindorfer MA, van der Horst H, Oostindie S, Beurskens FJ, Schuurman J, Zent CS, Burack R, Parren PW, Taylor RP (2016) Antibodies that efficiently form hexamers upon antigen binding can induce complement-dependent cytotoxicity under complement-limiting conditions. J Immunol 197:1762–1775

[44] Dall’Acqua WF, Woods RM, Ward ES, Palaszynski SR, Patel NK, Brewah YA, Wu H, Kiener PA, Langermann S (2002) Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences. J Immunol 169:5171–5180

[45] Dall’Acqua WF, Kiener PA, Wu H (2006) Properties of human IgG1 engineered for enhanced binding to the neonatal Fc receptor (FcRn). J Biol Chem 281:23514–23524

[46] Datta-Mannan A, Thangaraju A, Leung D, Tang Y, Witcher DR, Lu J, Wroblewski VJ (2015) Balancing charge in the complementarity determining regions of humanized mAbs without affecting pI reduces non-specific binding and improve pharmacokinetics. mAbs 7:483–493

[47] Davis PM, Abraham R, Xu L, Nadler SG, Suchard SJ (2007) Abatacept binds to the Fc receptor CD64 but does not mediate complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity. J Rheumatol 34:2204–2210

[48] de Jong RN, Beurskens FJ, Verploegen S, Strumane K, van Kampen MD, Voorhorst M, Horstman W, Engelberts PJ, Oostindie C, Wang G (2016) A novel platform for the potentiation of therapeutic antibodies based on antigen-dependent formation of IgG hexamers at the cell surface. PLoS Biol 14: e1002344.

[49] Desnoyers LR, Vasiljeva O, Richardson JH, Yang A, Menendez EEM, Liang TW, Wong C, Bessette PH, Kamath K, Moore SJ (2013) Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index. Sci Trans Med 5:207ra144.

[50] Devanaboyina SC, Lynch SM, Ober RJ, Ram S, Kim D, Puig-Canto A, Breen S, Kasturirangan S, Fowler S, Peng L (2013) The effect of pH dependence of antibody–antigen interactions on subcellular trafficking dynamics. mAbs 5:851–859

[51] Drake PM, Rabuka D (2015) An emerging playbook for antibodydrug conjugates: lessons learned from the laboratory and clinic suggest a strategy for improving efficacy and safety. Curr Opin Chem Biol 28:174–180

[52] Du T, Shi G, Li YM, Zhang JF, Tian HW, Wei YQ, Deng H, Yu DC (2014) Tumor-specific oncolytic adenoviruses expressing granulocyte macrophage colony-stimulating factor or anti-CTLA4 antibody for the treatment of cancers. Cancer Gene Ther 21:340–348

[53] Dutcher JP (2002) Current status of interleukin-2 therapy for metastatic renal cell carcinoma and metastatic melanoma. Oncology 16(Suppl 13):4–10

[54] Dyck L, Mills KHG (2017) Immune checkpoints and their inhibition in cancer and infectious diseases. Eur J Immunol. doi:10.1002/eji.201646875

[55] Egan TJ, Diem D, Weldon R, Neumann T, Meyer S, Urech DM (2016) Novel multispecific heterodimeric antibody format allowing modular assembly of variable domain fragments. mAbs 9:68–84

[56] Eigenbrot C, Fuh G (2013) Two-in-one antibodies with dual action Fabs. Curr Opin Chem Biol 17:400–405

[57] Ellebæk S, Brix S, Grandal M, Lantto J, Horak ID, Kragh M, Poulsen TT (2016) Pan-HER—An antibody mixture targeting EGFR, HER2 and HER3 abrogates preformed and ligand-induced EGFR homo- and heterodimers. Int J Cancer 139:2095–2105

[58] Erster O, Thomas JM, Hamzah J, Jabaiah AM, Getz JA, Schoep TD, Hall SS, Ruoslahti E, Daugherty PS (2012) Site-specific targeting of antibody activity in vivo mediated by disease-associated proteases. J Control Release 161:804–812

[59] Eshhar Z, Waks T, Gross G, Schindler DG (1993) Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA 90:720–724

[60] Esparis-Ogando A, Montero JC, Arribas J, Ocana A, Pandiella A (2016) Targeting the EGF/HER ligand- receptor system in cancer. Curr Pharm Des 22:5887–5898

[61] Fajardo CA, Guedan S, Rojas LA, Moreno R, Arias-Badia M, de Sostoa J, June CH, Alemany R (2017) Oncolytic adenoviral delivery of an EGFR-targeting T cell engager improves antitumor efficacy. Cancer Res 77:2052–2063

[62] Farrington GK, Caram-Salas N, Haqqani AS, Brunette E, Eldredge J, Pepinsky B, Antognetti G, Baumann E, Ding W, Garber E (2014) A novel platform for engineering blood-brain barriercrossing bispecific biologics. FASEB J 28:4764–4778

[63] Ferrara C, Brünker P, Suter T, Moser S, Püntener U, Umaña P (2006) Modulation of therapeutic antibody effector functions by glycosylation engineering: influence of golgi enzyme localization domain and co-expression of heterologous beta 1,4-N-acetylglucosaminyltransferase III and golgi alpha- mannosidase II. Biotechnol Bioeng 93:851–861

[64] Figueroa JA, Reidy A, Mirandola L, Trotter K, Suvorava N, Figueroa A, Konala V, Aulakh A, Littlefield L, Grizzi F (2015) Chimeric antigen receptor engineering: a right step in the evolution of adoptive cellular immunotherapy. Int Rev Immunol 34:54–187

[65] Fuchs SP, Desrosiers RC (2016) Promise and problems associated with the use of recombinant AAV for the delivery of anti-HIV antibodies. Methods Clin Dev 3:16068.

[66] Fuchs SP, Martinez-Navio Gao G, Desrosiers RC (2016) Recombinant AAV vectors for enhanced expression of authentic IgG. PLoS ONE 11:e0158009.

[67] Garrido MA, Valdayo MJ, Winkler DF, Titus JA, Hecht TT, Perez P, Segal DM, Wunderlich JR (1990) Refocusing the immune system to react with human tumors by targeting human lymphocytes with bispecific antibodies. Dev Biol Stand 71:33–42

[68] Giraud A, Ataman-Önal Y, Battail N, Piga N, Brand D, Mandrand B, Verrier B (1999) Generation of monoclonal antibodies to native human immunodeficiency virus type 1 envelope glycoprotein by immunization of mice with naked RNA. J Virol Methods 79:75–84

[69] Golay J, Da Roit F, Bologna L, Ferrara C, Leusen JH, Rambaldi A, Klein C, Introna M (2013) Glycoengineered CD20 antibody obinutuzumab activates neutrophils and mediates phagocytosis through CD16B more efficiently than rituximab. Blood 122:3482–3491

[70] Gorovits B, Krinos-Fiorotti C (2013) Proposed mechanism of offtarget toxicity for antibody-drug conjugates driven by mannose receptor uptake. Cancer Immunol Immunother 62:217–223

[71] Gray KA, Yates B, Seal RL, Wright MW, Bruford EA (2015) Genenames.org: the HGNC resources in 2015. Nucleic Acids Res 43(Database issue):D1079–D1085.

[72] Greenwood J, Clark M, Waldmann H (1993) Structural motifs involved in human IgG antibody effector functions. Eur J Immunol 23:1098–1104

[73] Greig JA, Calcedo R, Grant RL, Peng H, Medina-Jszek CA, Ahonkhai O, Qin Q, Roy S, Tretiakova AP, Wilson JM (2016) Intramuscular administration of AAV overcomes pre-existing neutralizing antibodies in rhesus macaques. Vaccine 34:6323–6329

[74] Gunasekaran K, Pentony M, Shen M, Garrett L, Forte C, Woodward A, Ng SB, Born T, Retter M, Manchulenko K, Sweet H, Foltz IN, Wittekind M, Yan W (2010) Enhancing antibody Fc heterodimer formation through electrostatic steering effects: applications to bispecific molecules and monovalent IgG. J Biol Chem 285:19637–19646

[75] Ha J-H, Kim J-E, Kim Y-S (2016) Immunoglobulin Fc heterodimer platform technology: from design to applications in therapeutic antibodies and proteins. Front Immunol.

[76] Hale M, Mesojednik T, Romano Ibarra GS, Sahni J, Bernard A, Sommer K, Scharenberg AM, Rawlings DJ, Wagner TA (2017) Engineering HIV-resistant, anti-HIV chimeric antigen receptor T cells. Mol Ther 25:570–579

[77] Halin C, Rondini S, Nilsson F, Berndt A, Kosmehl H, Zardi L, Neri D (2002) Enhancement of the antitumor activity of interleukin-12 by targeted delivery to neovasculature. Nat Biotechnol 20:264–269

[78] Harris SJ, Brown J, Lopez J, Yap TA (2016) Immuno-oncology combinations: raising the tail of the survival curve. Cancer Biol Med.

[79] Hawkins RE, Russel SJ, Winter G (1992) Selection of phage antibodies by binding affinity. Mimicking affinity maturation. J Mol Biol 226:889–896

[80] Hemmerle T, Neri D (2014) The antibody-based targeted delivery of interleukin-4 and 23 to the tumor neovasculature eradicates tumors in three mouse models of cancer. Int J Cancer 134:467–477

[81] Hernandez-Hoyos G, Sewell T, Bader R, Bannink J, Chenault RA, Daugherty M, Dasovich M, Fang H, Gottschalk R, Kumer J (2016) MOR209/ES414, a novel bispecific antibody targeting PSMA For the treatment of metastatic castration-resistant prostate cancer. Mol Cancer Ther 15:2155–2165

[82] Hess J, Ruf P, Lindhofer H (2012) Cancer therapy with trifunctional antibodies: linking innate and adaptive immunity. Future Oncol 8:73–85

[83] Hofman C, Seefried L, Jakob F (2016) Asfotase alfa: enzyme replacement for the treatment of bone disease in hypophosphatasia. Drugs Today (Barc) 52:271–285

[84] Holliger P, Winter G (1997) Diabodies: small bispecific antibody fragments. Cancer Immunol Immunother 45:128–130

[85] Holliger P, Prospero T, Winter G (1993) “Diabodies”: small bivalent and bispecific antibody fragments. Proc Natl Acad Sci USA 90:6444–6448

[86] Hughes C, Sette A, Seed M, D’Acquisto F, Manzo A, Vincent TL, Lim NH, Nissim A (2014) Targeting of viral interleukin-10 with an antibody fragment specific to damaged arthritic cartilage improves its therapeutic potency. Arthritis Res Ther 16:R151.

[87] Huston JS, Levinson D, Mudgett-Hunter M, Tai MS, Novotný M, Margolies MN, Ridge RJ, Bruccoleri RE, Haber E, Crea R, Oppermann H (1988) Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in Escherichia coli. Proc Natl Acad Sci USA 85:5879–5883

[88] Igawa T, Ishii S, Tachibana T, Maeda A, Higuchi Y, Shimaoka S, Moriyama C, Watanabe T, Takubo R, Doi Y (2010a) Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat Biotechnol 28:1203–1207

[89] Igawa T, Tsunoda H, Tachibana T, Maeda A, Mimoto F, Moriyama C, Nanami M, Sekimori Y, Nabuchi Y, Aso Y (2010b) Reduced elimination of IgG antibodies by engineering the variable region. Protein Eng Des Sel 23:385–392

[90] Igawa T, Maeda A, Haraya K, Tachibana T, Iwayanagi Y, Mimoto F, Higuchi Y, Ishii S, Tamba S, Hironiwa N (2013) Engineered monoclonal antibody with novel antigen-sweeping activity in vivo. PLoS One 8:e63236

[91] Igawa T, Haray K, Hattori K (2016) Sweeping antibody as a novel therapeutic antibody modality capable of eliminating soluble antigens from circulation. Immunol Rev 270:132–151

[92] Ihospice F, Delphine B, Belmant C, Patrick D, Aristeidis C, Fischer E, Laurent G, Bonnafus C, Viaud N, Represa A (2015) Sitespecific conjugation of monomethyl auristatin E to anti-CD30 antibodies improves their pharmacokinetics and therapeutic index in rodent models. Mol Pharm 12:1863–1871

[93] Ilan Y, Gingis-Velitski S, Ben Ya’aco A, Shabbat Y, Zolotarov L, Almon E, Shaaltiel Y (2017) A plant cell- expressed recombinant anti-TNF fusion protein is biologically activity in the gut and alleviates immune- mediated hepatitis and colitis. Immunobiol 222:544–551

[94] Johnson S, Burke S, Huang L, Gorlatov S, Li H, Wang W, Zhang W, Tuaillon N, Rainey J, Barat B (2010) Effector cell recruitment with novel Fv-based dual-affinity re-targeting protein leads to potent tumor cytolysis and in vivo B-cell depletion. J Mol Biol 399:436–449

[95] Jones PT, Dear PH, Foote J, Neuberger M, Winter G (1986) Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature 321:522–525

[96] Junutula JR, Raab H, Clark S, Bhakta S, Leipold DD, Weir S, Chen Y, Simpson M, Tsai SP, Dennis MS (2008) Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol 26:925–932

[97] Kanda Y, Yamane-Ohnuki N, Sakai N, Yamano K, Nakano R, Inoue M, Misaka H, Iida S, Wakitani M, Konno Y, Yano K, Shitara K, Hosoi S, Satoh M (2006) Comparison of cell lines for stable production of fucose- negative antibodies with enhanced ADCC. Biotechnol Bioeng 94:680–688

[98] Kim J-S, Choi D-K, Shin J-Y, Shin S-M, Park S-W, Cho H-S, Kim Y-S (2016) Endosomal acidic pH-induced conformational changes of a cytosol-penetrating antibody mediate endosomal escape. J Controlled Rel 235:165–175

[99] Kim BJ, Kim JH, Kim HS (2017) Survival benefit of immune checkpoint inhibitors according to the histology in non-small-cell lung cancer: a meta-analysis and review. Oncotarget.

[100] Kinder M, Greenplate AR, Grugan K, Bannish G, Perpetua M, Jordan RE, Strohl WR, Brezski RJ (2013) Engineered proteaseresistant antibodies with selectable cell-killing functions. J Biol Chem 288:30843–30854

[101] Kingwell K (2017) CAR T therapies drives into new terrain. Nat Rev Drug Discov 16:301–304

[102] Kipriyanov SM, Moldenhauer G, Schuhmacher J, Cochlovius B, von der Lieth C-W, Matys ER, Little M (1999) Bispecific tandem diabody for tumor therapy with improved antigen binding and pharmacokinetics. J Mol Biol 293:41–56

[103] Klein C, Sustmann C, Thomas M, Stubenrauch K, Croasdale R, Schanzer J, Brinkmann U, Kettenberger H, Regula JT, Schaefer W (2012) Progress in overcoming the chain association issue in bispecific heterodimeric IgG antibodies. mAbs 4:653–663

[104] Klein C, Waldhauer I, Nicolini VG, Freimoser-Grundschober A, Nayak T, Vugts DJ, Dunn C, Bolijn M, Benz J, Stihle M (2017) Cergutuzumab amunaleukin (CEA-IL2v), a CEA-targeted IL-2 variant-based immunocytokine for combination cancer immunotherapy: overcoming limitations of aldesleukin and conventional IL-2-based immunocytokines. Oncoimmunology 6: e1277306

[105] Kleinpeter P, Fend L, Thioudellet C, Geist M, Sfrontato N, Koerper V, Fahrner C, Schmitt D, Gantzer M, Remy-Ziller C (2016) Vectorization in an oncolytic vaccinia virus of an antibody, a Fab and a scFv against programmed cell death-1 (PD-1) allows their intratumoral delivery and an improved tumor- growth inhibition. Oncoimmunology 5:e1220467

[106] Konkar A, Suckow A, Hummer T, Chodorge M, Celeste A, Hornigold D, Naylor J, Jenkinson L, Feigh M, Agoram B (2016) MEDI4166: a PCSK9 Ab-GLP-1 fusion molecule that elicits robust antidiabetic and antihyperlipidaemic effects in rodents and non-human primates EASD. Abstract #1107

[107] Kontermann RE (2012) Dual targeting strategies with bispecific antibodies. Mabs 4:182–197

[108] Kontermann RE, Brinkmann U (2015) Bispecific antibodies. Drug Discov Today 20:838–847

[109] La Merie Publishing (2017) 2016 sales of recombinant therapeutic antibodies & proteins. Weikersheim 97990, Germany

[110] Labrijn AF, Aalberse RC, Schuurman J (2008) When binding is enough: nonactivating antibody formats. Curr Opin Immunol 20:479–485

[111] Labrijn AF, Meesters JI, de Goeij BE, van den Bremer ET, Neijssen J, van Kampen MD, Strumane K, Verploegen S, Kundu A, Gramer MJ (2013) Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange. Proc Natl Acad Sci USA 110:5145–5150

[112] Lalazar G, Mizrahi M, Turgeman I, Adar T, Ya’acov AB, Shabat Y, Nimer A, Hemed N, Zolotarovya L, Lichtenstein Y (2015) Oral administration of OKT3 Mab to patients with NASH, promotes regulatory T-cell induction, and alleviates insulin resistance: results of a phase IIa blinded placebo- controlled trial. J Clin Immunol 35:399–407

[113] Lazar AC, Wang L, Blättler WA, Amphlett G, Lambert JM, Zhang W (2005) Analysis of the composition of immunoconjugates using size-exclusion chromatography coupled to mass spectrometry. Rapid Commun Mass Spectrom 19:1806–1814

[114] Lazar GA, Dang W, Karki S, Vafa O, Peng JS, Hyun L, Chan C, Chung HS, Eivazi A, Yoder SC, Veilmetter J, Carmichael DF, Hayes RJ, Dahiyat BI (2006) Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci USA 103:4005–4010

[115] Lee KJ, Chow V, Weissman A, Tulpule S, Aldoss I, Akhtari M (2016) Clinical use of blinatumomab for B- cell acute lymphoblastic leukemia in adults. Ther Clin Risk Manag 12:1301–1310

[116] Leung KM, Batey S, Rowlands R, Isaac SJ, Jones P, Drewett V, Carvalho J, Gaspar M, Weller S, Medcalf M, Wydro MM, Pegram R, Mudde GC, Bauer A, Moulder K, Woisetschläger M, Tuna M, Haurum JS, Sun H (2015) A HER2-specific modified Fc fragment (Fcab) induces antitumor effects through degradation of HER2 and apoptosis. Mol Ther 23:1722–1733

[117] Lewis AD, Chen R, Montefiori DC, Johnson PR, Clark KR (2002) Generation of neutralizing activity against human immunodeficiency virus type 1 in serum by antibody gene transfer. J Virol 76:8769–8775

[118] Li J, Ji J, Holmes LM, Burgin KE, Barton LB, Yu X, Wagner TE, Wei Y (2004) Fusion protein from RGD peptide and Fc fragment of mouse immunoglobulin G inhibits angiogenesis in tumor. Cancer Gene Ther 11:363–370

[119] Li B, Tesar D, Boswell A, Cahaya H, Wong A, Zhang J, Gloria Meng Y, Eigenbrot C, Pantua H, Diao J (2014) Framework selection can influence pharmacokinetics of a humanized therapeutic antibody through differences in molecule charge. mAbs 6:1255–1264

[120] Li F, Emmerton KK, Jonas M, Zhang X, Miyamoto JB, Setter JR, Nicholas ND, Okeley NM, Lyon RP, Benjamin DR, Law C-L (2016) Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models. Cancer Res 76:2710–2719

[121] Liikanen I, Tahtinen S, Guse K, Gutmann T, Savola P, Oksanen M, Kanerva A, Hemminki A (2016) Oncolytic adenovirus expressing monoclonal antibody trastuzumab for treatment of HER2-positive cancer. Mol Cancer Ther 15:2259–2269

[122] Lim WA, June CH (2016) The principles of engineering immune cells to treat cancer. Cell 168:724–740

[123] Lim SI, Lukianov CI, Champion JA (2017) Self-assembled protein nanocarrier for intracellular delivery of antibody. J Controlled Rel 249:1–10

[124] Limberis MP, Adam VS, Wong G, Gren J, Kobasa D, Ross TM, Konbinger GP, Tretiakova A, Wilson JM (2013) Intranasal antibody gene transfer in mice and ferrets elicits broad protection against pandemic influenza. Sci Trans Med 5 (187):187ra72

[125] Liu L, Patel B, Ghanem MH, Bundoc V, Zheng Z, Morgan RA, Rosenberg SA, Dey B, Berger EA (2015) Novel CD4-based bispecific chimeric antigen receptor designed for enhanced anti-HIV potency and absence of HIV entry receptor activity. J Virol 89:6685–6694

[126] Liu L, Lam CK, Long V, Widjaja L, Yang Y, Li H, Jin L, Burke S, Gorlatov S, Brown J (2017) MGD011, a CD19 x CD3 dualaffinity retargeting bi-specific molecule incorporating extended circulating half-life for the treatment of B-cell malignancies. Clin Cancer Res 23:1506–1518

[127] Llewelyn MB, Hawkins RE, Russell SJ (1992) Discovery of antibodies. BMJ 305:1269–1272

[128] Lo M, Kim HS, Tong RK, Bainbridge TW, Vernes J-M, Zhang Y, Lin YL, Chung S, Dennis MS, Joy Y (2017) Effector attenuating substitutions that maintain antibody stability and reduce toxicity in mice. J Biol Chem 292:3900–3909

[129] Lönn P, Kacsinta AD, Cui X-S, Hamil AS, Kaulich M, Gogoi K, Dowdy SF (2016) Enhancing endosomal escape for intracellular delivery of macromolecular biologic therapeutics. Nat Sci Rep 8 (6):32301.

[130] Luke T, Wu H, Zhao J, Channappanavar R, Coleman CM, Jiao J-A, Matsushita H, Liu Y, Postnikova EN, Ork BL (2016) Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS- CoV in vivo. Sci Trans Med 8:326ra21.

[131] Lum LG, Thakur A (2011) Targeting T cells with bispecific antibodies for cancer therapy. BioDrugs 25:365–379

[132] Mack M, Riethmüller G, Kufer P (1995) A small bispecific antibody construct expressed as a functional single-chain molecule with high tumor cell cytotoxicity. Proc Natl Acad Sci USA 92:7021–7025

[133] MacLeod DT, Antony J, Martin AJ, Moser RJ, Hekele A, Wetzel KJ, Brown AW, Triggiano MA, Hux JA, Pham CD (2017) Integration of a CD19 CAR into the TCR alpha chain locus streamlines production of allogeneic gene-edited CAR T cells. Mol Ther 25:949–961

[134] Madrenas J, Chau LA, Teft WA, Wu PW, Jussif J, Kasaian M, Carreno BM, Ling V (2004) Conversion of CTLA-4 from inhibitor to activator of T cells with a bispecific tandem single-chain Fc ligand. J Immunol 172:5948–5956

[135] Malphettes L, Freyvert Y, Chang J, Liu PQ, Chan E, Miller JC, Zhou Z, Nguyen T, Tsai C, Snowden AW, Collingwood TN, Gregory PD, Cost GJ (2010) Highly efficient deletion of FUT8 in CHO cell lines using zinc-finger nucleases yields cells that produce completely nonfucosylated antibodies. Biotechnol Bioeng 106:774–783

[136] Marschall ALJ, Zhang C, Frenzel A, Schirrmann T, Hust M, Perez F, Dübel S (2014) Delivery of antibodies to the cytosol. Debunking the myths. mAbs 6:943–956

[137] Matsushita H, Sano A, Wu H, J-aJiao, Kasinathan P, Sullivan EJ, Wang Z, Kuroiwa Y (2014) Triple immunoglobulin gene knockout transchromosomic cattle: bovine lambda cluster deletion and its effect on fully human polyclonal antibody production. PLoS ONE 9:e90383.

[138] Matsushita H, Sano A, Wu H, Wang Z Jiao, J-a, Kasinathan P, Sullivan EJ, Kuroiwa Y (2015) Species- specific chromosome engineering greatly improves fully human polyclonal antibody production profile in cattle. PLoS ONE 10:e0130699.

[139] McCracken MN, Cha AC, Weissman IL (2015) Molecular pathways: activating T cells after cancer cell phagocytosis from blockade of CD47 “don’t eat me” signals. Clin Cancer Res 21:3597–3601

[140] Merchant AM, Zhu Z, Yuan JQ, Goddard A, Adams CW, Presta LG, Carter P (1998) An efficient route to human bispecific IgG. Nat Biotechnol 16:677–681

[141] Millan JL, Narisawa S, Lemire I, Loisel TP, Boileau G, Leonard P, Gramatikova S, Terkeltaub R, Pleshko Camacho NMcKee MD (2008) Enzyme replacement therapy for murine hypophosphatasia. J Bone Min Res 23:777–787

[142] Milstein C, Cuello AC (1983) Hybrid hybridomas and their use in immunohistochemistry. Nature 305:537–540

[143] Mire CE, Geisbert JB, Agans KN, Thi EP, Lee AC, Fenton KA, Geisbert TW (2016) Passive immunotherapy: assessment of convalescent serum against ebola virus makona infection in nonhuman primates. J Infect Dis 214(Suppl 3):S367–S374

[144] Moore PA, Zhang W, Rainey GJ, Burke S, Li H, Huang L, Gorlatov S, Veri MC, Aggarwal S, Yang Y (2011) Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B- cell lymphoma. Blood 117:4542–4551

[145] Moretti P, Skegro D, Ollier R, Wassmann P, Aebischer C, Laurent T, Schmid-Printz M, Giovannini R, Blein S, Bertschinger M (2013) BEAT® the bispecific challenge: a novel and efficient platform for the expression of bispecific IgGs. BMC Proc 7(Suppl 6):O9.

[146] Morrison SL, Johnson MJ, Herzenberg LA, Oi VT (1984) Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc Natl Acad Sci USA 81:6851–6855

[147] Mueller JP, Giannoni MA, Hartman SL, Elliott EA, Squinto SP, Mathis LA, Evans MJ (1997) Humanized porcine VCAM-specific monoclonal antibodies with chimeric IgG2/G4 constant regions block human leukocyte binding to porcine endothelial cells. Mol Immunol 34:441–452

[148] Neri D, Sondel PM (2016) Immunocytokines for cancer treatment: past, present and future. Curr Opin Immunol 40:96–102

[149] Nesspor TC, Raju TS, Chin C-N, Vafa O, Brezski RJ (2012) Avidity confers FcγR binding and immune effector fuction to aglycosylated IgG1. J Mol Recognit 25:147–154

[150] Niewoehner J, Bohrmann B, Collin L, Urich E, Sade H, Maier P, Rueger P, Stracke JO, Lau W, Tissot AC (2014) Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron 81:49–60

[151] Ochoa MC, Minute L, Rodriguez I, Garasa S, Perez-Ruiz E, Inoges S, Melero I, Berraondo P (2017) Antibody-dependent cell cytotoxicity: immunotherapy strategies enhancing effector NK cells. Immunol Cell Biol 95:347–355

[152] Panowski S, Bhakta S, Raab H, Polakis P, Junutula JR (2014) Sitespecific antibody drug conjugates for cancer therapy. mAbs 6:34–45

[153] Park JH, Brentjens RJ (2010) Adoptive immunotherapy for B-cell malignancies with autologous chimeric antigen receptor modified tumor targeted T cells. Discov Med 9:277–288

[154] Pasche N, Wuhlfard S, Pretto F, Carugati E, Neri D (2012) The antibody-based delivery of interleukin-12 to the tumor neovasculature eradicates murine models of cancer in combination with paclitaxel. Clin Cancer Res 18:4092–4103

[155] Penichet ML, Morrison SL (2001) Antibody–cytokine fusion proteins for the therapy of cancer. J Immunol Methods 248:91–101

[156] Perez HL, Cardarelli PM, Deshpande S, Gangwar S, Schroeder GM, Vite GD, Borzilleri RM (2014) Antibody-drug conjugates: current status and future directions. Drug Disc Today 19:869–981

[157] Polu KR, Lowman HB (2014) Probody therapeutics for targeting antibodies to diseased tissue. Expert Opin Biol Ther 14:1049–1053

[158] Poul M-A, Becerril B, Nielsen UB, Morisson P, Marks JD (2000) Selection of tumor-specific internalizing antibodies form phage libraries. J Mol Biol 301:1149–1161

[159] Queen C, Schneider WP, Selick HE, Payne PW, Landolfi NF, Duncan JF, Avdalovic NM, Levitt M, Junghans RP, Waldmann TA (1989) A humanized antibody that binds to the interleukin 2 receptor. Proc Natl Acad Sci USA 86:10029–10033

[160] Rafiq S, Purdon TJ, Daniyan AF, Koneru M, Dao T, Liu C, Scheinberg DA, Brentjens RJ (2017) Optimized T-cell receptormimic chimeric antigen receptor T cells directed toward the intracellular Wilms tumor 1 antigen. Leukemia.

[161] Raju TS, Strohl WR (2013) Potential therapeutic roles for antibody mixtures. Expert Opin Biol Ther 13:1347–1352

[162] Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y (2017a) Multiplex genome editing to generate universal CAR Tcells resistant to PD-1 inhibition. Clin Cancer Res 23:2255–2266

[163] Ren J, Zhang X, Liu X, Fang C, Jiang S, June CH, Zhao Y (2017b) A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget 8:17002–17011

[164] Reusch U, Duell J, Ellwanger K, Herbrecht C, Knackmuss SH, Fucek I, Eser M, McAleese F, Molkenthin V, Gall FL, Topp M, Little M, Zhukovsky EA (2015) A tetravalent bispecific TandAb (CD19/CD3), AFM11, efficiently recruits Tcells for the potent lysis of CD19(+) tumor cells. mAbs 7:584–604

[165] Ridgeway JB, Presta LG, Carter P (1996) ‘Knobs-into-holes’ engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng 9:617–621

[166] Robbie GJ, Criste R, Dall’acqua WF, Jensen K, Patel NK, Losonsky GA, Griffen MP (2013) A novel investigational Fc-modified humanized antibody, motavizumab-YTE, has an extended halflife in healthy adults. Antimicrob Agents Chemother 57:6147–6153

[167] Roopenian DC, Akilesh S (2007) FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 7:715–725

[168] Root AR, Cao W, Li B, LaPan P, Meade C, Sanford J, Jin M, O’Sullivan C, Cummins E, Lambert M (2016) Development of PF-06671008, a highly potent anti-P-cadherin/anti-CD3 bispecific DART molecule with extended half-life for the treatment of cancer. Antibodies 5:6.

[169] Rother RP, Rollins SA, Mojcik CJ, Brodsky RJ, Bell L (2007) Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol 25:1256–1264

[170] Ruella M, Gill S (2015) How to train your T cell: genetically engineered chimeric antigen receptor T cells versus bispecific T-cell engagers to target CD19 in B acute lymphoblastic leukemia. Expert Opin Biol Ther 15:761–766

[171] Ruella M, June CH (2016) Chimeric antigen receptor Tcells for B cell neoplasms: choose the right CAR for you. Curr Hematol Malig Rep 11:368–384

[172] Sahu GK, Sango K, Selliah N, Ma Q, Skowron G, Junghans RP (2013) Anti-HIV designer T cells progressively eradicate a latently infected cell line by sequentially inducing HIV reactivation then killing the newly gp120-positive cells. Virology 446:268–275

[173] Sampei Z, Igawa T, Soeda T, Okuyama-Nishida Y, Moriyama C, Wakabayashi T, Tanaka E, Muto A, Kojima T, Kitazawa T (2013) Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of Factor VIII cofactor activity. PLoS ONE 8:e57479.

[174] Satta A, Mezzanzanica D, Turatti F, Canevari S, Figini M (2013) Redirection of T-cell effector functions for cancer therapy: bispecific antibodies and chimeric antigen receptors. Future Oncol 9:527–539

[175] Schirdewahn T, Grabowski J, Sekyere SO, Bremer B, Wranke A, Lunemann S, Schlaphoff V, Kirschner J, Hardtke S, Manns MP (2017) The third signal cytokine IL-12 rather than immune checkpoint inhibitors contribute to the functional restoration of hepatitis D virus-specific T-cells. J Infect Dis 215:139–149

[176] Schlereth B, Fichtner I, Lorenczewski G, Kleindienst P, Brischwein K, da Silva A, Kufer P, Lutterbuese R, Junghahn I, Kasimir-Bauer S (2005) Eradication of tumors from a human colon cancer cell line and from ovarian cancer metastases in immunodeficient mice by a single-chain Ep-CAM-/CD3-bispecific antibody construct. Cancer Res 65:2882–2889

[177] Schlothauer T, Herter S, Koller CF, Grau-Richards S, Steinhart V, Spick C, Kubbies M, Klein C, Umaña P, Mössner E (2016) Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions. Prot Eng Des Sel 29:457–466

[178] Schnepp BC, Johnson PR (2014a) Adeno-associated virus delivery of broadly neutralizing antibodies. Curr Opin HIV AIDS 9:250–256

[179] Schnepp BC, Johnson PR (2014b) Vector-mediated in vivo antibody expression. Microbiol Spect 2(4):AID-0016–2014.

[180] Seeliger D, Schulz P, Litzenburger T, Spitz J, Hoerer S, Blech M, Enenkel B, Studts JM, Garidel P, Karow AR (2015) Boosting antibody developability through rational sequence optimization. mAbs 7:505–515

[181] Sharkey RM, Rossi EA, Chang C-H, Goldenberg DM (2010) Improved cancer therapy and molecular imaging with multivalent, multispecific antibodies. Cancer Biother Radiopharm 25:1–12

[182] Shi Y, Fan X, Deng H, Brezski RJ, Rycyzyn M, Jordan RE, Strohl WR, Zou Q, Zhang N, An Z (2015) Trastuzumab triggers phagocytic killing of high HER2 cancer cells by interaction with FcγRIV on immune cells. J Immunol 194:4379–4386

[183] Shields RL, Namenuk AK, Hog K, Meng YG, Rae J, Briggs J, Xie D, Lai J, Stadlen A, Li B, Fox JA, Presta LG (2001) High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. J Biol Chem 276:6591–6604

[184] Shields RL, Lai J, Keck R, O’Connell LY, Hong K, Meng YG, Weikert SH, Presta LG (2002) Lack of fructose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma Rlll and antibody- dependent cellular toxicity. J Biol Chem 277:26733–26740

[185] Siegmund V, Piater B, Zakeri B, Eichhorn T, Fischer F, Deutsch C, Becker S, Toleikis L, Hock B, Betz UAK, Kolmar H (2016) Spontaneous isopeptide bond formation as a powerful tool for engineering site- specific antibody-drug conjugates. Sci Rep 6:39291.

[186] Silacci M, Lembke W, Woods R, Attinger-Toller I, Baenziger-Tobler N, Batey S, Santimaria R, von der Bey U, Koenig-Friedrich S, Zha W, Schlereth B, Locher M, Bertschinger J, Grabulovski D (2016) Discovery and characterization of COVA322, a clinical stage bispecific TNF/IL-17A inhibitor for the treatment of inflammatory diseases. mAbs 8:141–149

[187] Singh AP, Sharma S, Shah DK (2016) Quantitative characterization of in vitro bystander effect of antibody-drug conjugates. J Pharmacokinet Pharmacodyn 43:567–582

[188] Smith EJ, Olson K, Haber LJ, Varghese B, Duramad P, Tustian AD, Oyejide A, Kirshner JR, Canova L, Menon J, Principio J, MacDonald D, Kantrowitz J, Papadopoulos N, Stahl N, Yancopoulos GD, Thurston G, Davis S (2015) A novel, native-format bispecific antibody triggering T-cell killing of B-cells is robustly active in mouse tumor models and cynomolgus monkeys. Sci Rep 5:17943

[189] Smith AJ, Oertle J, Warren D, Prato D (2016) Chimeric antigen receptor (CAR) T cell therapy for malignant cancers: summary and perspective. J Cell Immunol 2:59–68

[190] Sondermann P, Szymkowski DE (2016) Harnessing Fc receptor biology in the design of therapeutic antibodies. Curr Opin Immunol 40:78–87

[191] Spiess C, Zhai Q, Carter PJ (2015) Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol Immunol 67:95–106

[192] Stewart MP, Sharei A, Ding X, Sayay G, Langer R, Jensen KF (2016) In vitro and ex vivo strategies for intracellular delivery. Nature 538:183–192

[193] Storz U (2014) Rituximab. How approval history is reflected by a corresponding patent filing strategy. mAbs 6:820–837

[194] Strohl WR (2009) Optimization of Fc-mediated effector functions of monoclonal antibodies. Curr Opin Biotechnol 20:685–691

[195] Strohl WR (2011) Isotype selection and Fc engineering: design and construction of fit-for-purpose therapeutic antibodies. In: Wood C (ed) Antibody drug discovery. Imperial College Press, London, pp 147–220

[196] Strohl WR (2015) Fusion proteins for half-life extension of biologics as a strategy to make biobetters. BioDrugs 29:215–239

[197] Strohl WR, Strohl LM (2012). Therapeutic antibody engineering: current and future advances driving the strongest growth area in the pharma industry. Woodhead Publishing Series in Biomedicine No. 11 (Cambridge). ISBN 9781907568374. Published Oct 22, 2012

[198] Strop P, Ho W-H, Boustany LM, Abdiche YN, Lindquist KC, Farias SE, Rickert M, Appah CT, Pascua E, Radcliffe T (2012) Generating bispecific human IgG1 and IgG2 antibodies from any antibody pair. J Mol Biol 420:204–219

[199] Sun L-M, Liu Y-C, Li W, Liu S, Liu H-X, Li L-W, Ma R (2017) Nivolumab effectively inhibit platinum- resistant ovarian cancer cells via induction of cell apoptosis and inhibition of ADAM17 expression. Eur Rev Med Pharmacol Sci 21:1198–1205

[200] Suzuki M, Curran KJ, Cheung N-KV (2015) Chimeric antigen receptos and bispecific antibodies to retarget T cells in pediatric oncology. Pediatr Blood Cancer 62:1326–1336

[201] Tanoue K, Shaw AR, Watanabe N, Porter C, Rana B, Gottschalk S, Brenner M, Suzuki M (2017) Armed oncolytic adenovirus expressing PD-L1 mini-body enhances anti-tumor effects of chimeric antigen receptor T-cells in solid tumors. Cancer Res 77:2040–2051

[202] Taylor RP, Lindorfer MA (2016) Cytotoxic mechanisms of immunotherapy: Harnessing complement in the action of antitumor monoclonal antibodies. Semin Immunol 28:309–316

[203] Teicher BA (2009) Antibody-drug conjugate targets. Curr Cancer Drug Targets 9:982–1004

[204] Thompson P, Ezeadi E, Hutchinson I, Fleming R, Bezabeh B, Lin J, Mao S, Chen C, Masterson L, Zhong H (2016) Straightforward glycoengineering approach to site-specific antibodypyrrolobenzodiazepine conjugates. ACS Med Chem Lett 7:1005–1008

[205] Throsby M, Logtenberg T, De Kruif J(2015) Generation of binding molecules. US 9145588 B2, Published Sept 29, 2015

[206] Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27:450–561

[207] Tsuchikama K, An Z (2016) Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein Cell (this issue)

[208] Tustian AD, Endicott C, Adams B, Mattila J, Bak H (2016) Development of purification processes for fully human bispecific antibodies based upon modification of protein A binding avidity. mAbs 8:828–838

[209] Umaña P, Jean-Mairet J, Moudry R, Amstutz H, Bailey JE (1999) Engineered glycoforms of an anti- neuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity. Nat Biotechnol 17:176–180

[210] Vafa O, Gilliland GL, Brezski RJ, Strake B, Wilkinson T, Lacy ER, Scallon B, Teplyakov A, Malia T, Strohl WR (2013) An engineered silent Fc variant of an IgG eliminates all immune effector functions via structural perturbations. Methods 65:114–126

[211] van der Stegen SJC, Hamieh M, Sadelain M (2015) The pharmacology of second-generation chimeric antigen recpetors. Nat Rev Drug Discov 14:499–509

[212] van der Vlist M, Kuball J, Radstake TRD, Meyaard L (2016) Immune checkpoints and rheumatic diseases: what can cancer immunotherapy teach us?Nat Rev Rheumatol 12:593–604

[213] Von Kreudenstein TS, Escobar-Carbrera E, Lario PI, D’Angelo I, Brault K, Kelly J, Durocher Y, Baardsnes J, Woods RJ, Xie MH, Girod PA, Suits MD, Boulanger MJ, Poon DK, Ng GY, Dixit SB (2013) Improving biophysical properties of a bispecific antibody scaffold to aid developability: quality by molecular design. mAbs 5:646–654

[214] Walker MR, Lund J, Thompson KM, Jefferis R (1989) Aglycosylation of human IgG1 and IgG3 monoclonal antibodies can eliminate recognition by human cells expressing FcγRI and/or FcγRII receptors. Biochem J 259:347–353

[215] Wang Y, Yan Z, Huang Y, Qiu C, Chen X, Hu Y, Meng Q, Wei J (2017a) Study of natural antibodies against vascular endothelial growth factor receptor 1 in hepatocarcinoma. Am J Cancer Res 7:603–609

[216] Wang B, Kothambawala T, Hinton P, Ng D, Saini A, Baliga R, Keyt B (2017b) Multimeric anti-DR5 IgM antibody displays potent cytotoxicity in vitro and promotes tumor regression in vivo. Abstract no 1702 AACR Ann Meet 2017, April 1–5, 2017

[217] Ward ES, Güssow D, Griffiths AD, Jones PT, Winter G (1989) Binding activities of a repertoire of single immunoglobulin variable domains secreted from Escherichia coli. Nature 341:544–546

[218] Webster CI, Caram-Salas N, Haqqani AS, Thom G, Brown L, Rennie K, Yogi A, Costain W, Brunette E, Stanimirovic DB (2016) Brain penetration, target engagement, and disposition of the bloodbrain barrier-crossing bispecific antibody antagonist of metabotropic glutamate receptor type 1. FASEB J 30:1927–1940

[219] Wu C, Ting H, Grinnell C, Bryant S, Miller R, Clabbers A, Bose S, McCarthy D, Zhu RR, Santora L (2007) Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin. Nat Biotechnol 25:1290–1297

[220] Yamane-Ohnuki N, Kinoshita S, Inoue-Urakubo M, Kusunoki M, Iida S, Nakano R, Wakitani M, Niwa R, Sakurada M, Uchida K (2004) Establishment of FUT8 knockout Chinese hamster ovary cells; an ideal host cell line for producing completely defucosylated antibodies with enhanced antibody- dependent cellular cytotoxicity. Biotechnol Bioeng 87:614–622

[221] Yang L, Wang P (2014) Passive immunization against HIV/AIDS by antibody gene transfer. Viruses 6:428–447

[222] Yu YJ, Zhang Y, Kenrick M, Hoyte K, Luk W, Lu Y, Atwal J, Elliott JM, Prabhu S, Watts RJ, Dennis MS (2011) Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Trans Med 3:84ra44

[223] Yu YJ, Atwal JK, Zhang Y, Tong RK, Wildsmith KR, Tan C, Bien-Ly N, Hersom M, Maloney JA, Meilandt WJ (2014) Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates. Sci Trans Med 6:261ra154. 3009835

[224] Yurkovetskiy AV, Yin M, Bodyak N, Stevenson CA, Thomas JD, Hammond CE, Qin LL, Zhu B, Gumerov DR, Ter-Ovanesyan E (2015) A polymer-based antibody-vinca drug conjugate platform: characterization and preclinical efficacy. Cancer Res 75:3365–3372

[225] Zalevsky J, Chamberlain AK, Horton HM, Karki S, Leung IWL, Sproule TJ, Lazar GA, Roopenian DC, Desjarlais JR (2010) Enhanced antibody half-life improves in vivo activity. Nat Biotechnol 28:157–159

[226] Zeidler R, Reisbach G, Wollenberg B, Lang S, Chaubel S, Schmitt B, Lindhofer H (1999) Simultaneous activation of T cells and accessory cells by a new class of intact bispecific antibody results in efficient tumor cell killing. J Immunol 163:1246–1252

[227] Zeltsman M, Mayor M, Jones DR, Adusumilli PS (2016) Surgical immune interventions for solid malignancies. Am J Surg 212:682–690

[228] Zhang X-Y, Zhang P-Y (2016) Receptor tyrosine kinases in carcinogenesis (Review). Oncol Lett 12:3679–3682

[229] Zhou Y, Zou H, Zhang S, Marks JD (2010) Internalizing cancer antibodies from phage libraries selected on tumor cells and yeast displayed tumor antigens. J Mol Biol 404:88–99

[230] Zhukovsky EA, Morse RJ, Maus MV (2016) Bispecific antibodies and CARs: generalized immunotherapeutics harnessing T cell redirection. Curr Opin Immunol 40:24–35

RIGHTS & PERMISSIONS

2017 The Author(s) 2017. This article is an open access publication