Anti-PD1 ‘SHR-1210ʹ aberrantly targets pro-angiogenic receptors and this polyspecificity can be ablated by paratope refinement

References

• Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, Iyer AK. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol. 2017;8:561. doi:10.3389/fphar.2017.00561.
   PubMed Web of Science ®Google Scholar
• Nelson AL, Dhimolea E, Reichert JM. Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov. 2010;9:767–774. doi:10.1038/nrd3229.
   PubMed Web of Science ®Google Scholar
• Kaplon H, Reichert JM. Antibodies to watch in 2018. MAbs. 2018;10:183–203. doi:10.1080/19420862.2018.1415671.
   PubMed Web of Science ®Google Scholar
• Mo H, Huang J, Xu J, Chen X, Wu D, Qu D, Wang X, Lan B, Wang X, Xu J, et al. Safety, anti-tumour activity, and pharmacokinetics of fixed-dose SHR-1210, an anti-PD-1 antibody in advanced solid tumours: a dose-escalation, phase 1 study. Br J Cancer. 2018. doi: 10.1038/s41416-018-0100-3.
   Web of Science ®Google Scholar
• Burnet FM. A modification of Jerne’s theory of antibody production using the concept of clonal selection. CA Cancer J Clin. 1976;26:119–121.
   PubMedGoogle Scholar
• Bumbaca D, Wong A, Drake E, Reyes Ii AE, Lin BC, Stephan J-P, Desnoyers L, Shen B-Q, Dennis MS. Highly specific off-target binding identified and eliminated during the humanization of an antibody against FGF receptor 4. MAbs. 2014;3:376–386. doi:10.4161/mabs.3.4.15786.
   Web of Science ®Google Scholar
• Tiller T, Schuster I, Deppe D, Siegers K, Strohner R, Herrmann T, Berenguer M, Poujol D, Stehle J, Stark Y, et al. A fully synthetic human Fab antibody library based on fixed VH/VL framework pairings with favorable biophysical properties. MAbs. 2013;5:445–470. doi:10.4161/mabs.24218.
   PubMed Web of Science ®Google Scholar
• Townsend S, Fennell BJ, Apgar JR, Lambert M, McDonnell B, Grant J, Wade J, Franklin E, Foy N, Ní Shúilleabháin D, et al. Augmented binary substitution: single-pass CDR germ-lining and stabilization of therapeutic antibodies. Proc Natl Acad Sci U.S.A. 2015;112:15354–15359. doi:10.1073/pnas.1510944112.
   PubMed Web of Science ®Google Scholar
• Bogen B, Ruffini P. Review: to what extent are T cells tolerant to immunoglobulin variable regions? Scand J Immunol. 2009;70:526–530. doi:10.1111/j.1365-3083.2009.02340.x.
   PubMed Web of Science ®Google Scholar
• Eyerman MC, Zhang X, Wysocki LJ. T cell recognition and tolerance of antibody diversity. J Immunol. 1996;157:1037–1046.
   PubMed Web of Science ®Google Scholar
• Manz BN, Jackson BL, Petit RS, Dustin ML, Groves J. T-cell triggering thresholds are modulated by the number of antigen within individual T-cell receptor clusters. Proc Natl Acad Sci U.S.A. 2011;108:9089–9094. doi:10.1073/pnas.1018771108.
   PubMed Web of Science ®Google Scholar
• Avery LB, Wade J, Wang M, Tam A, King A, Piche-Nicholas N, Kavosi MS, Penn S, Cirelli D, Kurz JC, et al. Establishing in vitro in vivo correlations to screen monoclonal antibodies for physicochemical properties related to favorable human pharmacokinetics. MAbs. 2018;10:244–255. doi:10.1080/19420862.2017.1417718.
   PubMed Web of Science ®Google Scholar
• Granier C, De Guillebon E, Blanc C, Roussel H, Badoual C, Colin E, Saldmann A, Gey A, Oudard S, Tartour E. Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer. ESMO Open. 2017;2:e000213. doi:10.1136/esmoopen-2017-000213.
   PubMed Web of Science ®Google Scholar
• Finton KA, Larimore K, Larman HB, Friend D, Correnti C, Rupert PB, Elledge SJ, Greenberg PD, Strong RK, Trkola A. Autoreactivity and exceptional CDR plasticity (but not unusual polyspecificity) hinder elicitation of the anti-HIV antibody 4E10. PLoS Pathog. 2013;9:e1003639. doi:10.1371/journal.ppat.1003639.
   PubMed Web of Science ®Google Scholar
• Betts A, Keunecke A, van Steeg TJ, van der Graaf PH, Avery LB, Jones H, Berkhout J. Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach. MAbs. 2018;10:751–764. doi:10.1080/19420862.2018.1462429.
   PubMed Web of Science ®Google Scholar
• Piche-Nicholas NM, Avery LB, King AC, Kavosi M, Wang M, O’Hara DM, Tchistiakova L, Katragadda M. Changes in complementarity-determining regions significantly alter IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics. MAbs. 2018;10:81–94. doi:10.1080/19420862.2017.1389355.
   PubMed Web of Science ®Google Scholar
• Kohli N, Jain N, Geddie ML, Razlog M, Xu L, Lugovskoy AA. A novel screening method to assess developability of antibody-like molecules. MAbs. 2015;7:752–758. doi:10.1080/19420862.2015.1048410.
   PubMed Web of Science ®Google Scholar
• Hotzel I, Theil FP, Bernstein LJ, Prabhu S, Deng R, Quintana L, Lutman J, Sibia R, Chan P, Bumbaca D, et al. A strategy for risk mitigation of antibodies with fast clearance. MAbs. 2012;4:753–760. doi:10.4161/mabs.22189.
   PubMed Web of Science ®Google Scholar
• Jain T, Sun T, Durand S, Hall A, Houston NR, Nett JH, Sharkey B, Bobrowicz B, Caffry I, Yu Y, et al. Biophysical properties of the clinical-stage antibody landscape. Proc Natl Acad Sci U.S.A. 2017;114:944–949. doi:10.1073/pnas.1616408114.
   PubMed Web of Science ®Google Scholar
• Boye E, Olsen BR. Signaling mechanisms in infantile hemangioma. Curr Opin Hematol. 2009;16:202–208. doi:10.1097/MOH.0b013e32832a07ff.
   PubMed Web of Science ®Google Scholar
• Ma D, Baruch D, Shu Y, Yuan K, Sun Z, Ma K, Hoang T, Fu W, Min L, Lan Z-S, et al. Using protein microarray technology to screen anti-ERCC1 monoclonal antibodies for specificity and applications in pathology. BMC Biotechnol. 2012;12:88. doi:10.1186/1472-6750-12-88.
   PubMed Web of Science ®Google Scholar
• Turner L, Lavstsen T, Berger SS, Wang CW, Petersen JE, Avril M, Brazier AJ, Freeth J, Jespersen JS, Nielsen MA, et al. Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature. 2013;498:502–505. doi:10.1038/nature12216.
   PubMed Web of Science ®Google Scholar
• Espinosa Lara P, Medina-Puente C, Riquelme Oliveira A, Jimenez-Reyes J. Eruptive cherry angiomas developing in a patient treated with ramucirumab. Acta Oncol. 2018;57:709–711. doi:10.1080/0284186X.2017.1410287.
   PubMed Web of Science ®Google Scholar
• Lim YH, Odell ID, Ko CJ, Choate KA. Somatic p.T771R KDR (VEGFR2) mutation arising in a sporadic angioma during ramucirumab therapy. JAMA Dermatol. 2015;151:1240–1243. doi:10.1001/jamadermatol.2015.1925.
   PubMed Web of Science ®Google Scholar
• Peterson YK, Nasarre P, Bonilla IV, Hilliard E, Samples J, Morinelli TA, Hill EG, Klauber-DeMore N. Frizzled-5: a high affinity receptor for secreted frizzled-related protein-2 activation of nuclear factor of activated T-cells c3 signaling to promote angiogenesis. Angiogenesis. 2017;20:615–628. doi:10.1007/s10456-017-9574-5.
   PubMed Web of Science ®Google Scholar
• Molfetta R, Quatrini L, Santoni A, Paolini R. Regulation of NKG2D-dependent NK cell functions: the yin and the yang of receptor endocytosis. In J Mol Sci. 2017;18:1677.
   Web of Science ®Google Scholar
• Sutherland CL, Chalupny NJ, Schooley K, VandenBos T, Kubin M, Cosman D. UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells. J Immunol. 2002;168:671–679.
   PubMed Web of Science ®Google Scholar
• Endpoints. Incyte grabs a new PD-1 checkpoint drug in $900M deal with MacroGenics. In Carroll J, editor. 2017. https://endpts.com/incyte-grabs-a-new-pd-1-checkpoint-drug-in-900m-deal-with-macrogenics/
   Google Scholar
• Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status and future directions. Lancet. 2016;388:518–529. doi:10.1016/S0140-6736(15)01088-0.
   PubMed Web of Science ®Google Scholar
• Notkins AL. Polyreactivity of antibody molecules. Trends Immunol. 2004;25:174–179. doi:10.1016/j.it.2004.02.004.
   PubMed Web of Science ®Google Scholar
• Rios-Doria J, Harper J, Rothstein R, Wetzel L, Chesebrough J, Marrero AM, Chen C, Strout P, Mulgrew K, McGlinchey K, et al. Antibody-drug conjugates bearing pyrrolobenzodiazepine or tubulysin payloads are immunomodulatory and synergize with multiple immunotherapies. Cancer Res. 2017. doi: 10.1158/0008-5472.CAN-16-2854.
   PubMed Web of Science ®Google Scholar
• Root A, Cao W, Li B, LaPan P, Meade C, Sanford J, Jin M, O’Sullivan C, Cummins E, Lambert M, et al. 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. 2016;5:6. doi:10.3390/antib5010006.
   Web of Science ®Google Scholar
• Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics. 2016;3:16011. doi:10.1038/mto.2016.11.
   PubMed Web of Science ®Google Scholar
• Vugmeyster Y, Guay H, Szklut P, Qian MD, Jin M, Widom A, Spaulding V, Bennett F, Lowe L, Andreyeva T, et al. In vitro potency, pharmacokinetic profiles, and pharmacological activity of optimized anti-IL-21R antibodies in a mouse model of lupus. MAbs. 2010;2:335–346.
   PubMed Web of Science ®Google Scholar
• Finlay WJ, Bloom L, Cunningham O. Optimized generation of high-affinity, high-specificity single-chain Fv antibodies from multiantigen immunized chickens. Methods Mol Biol. 2011;681:383–401. doi:10.1007/978-1-60761-913-0_21.
   PubMedGoogle Scholar