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===First Human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers===
===First Human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers===
====Serum ch-mAb7F9 concentration====
====Serum ch-mAb7F9 concentration====
-
====immunogenicity analyses====
+
====Immunogenicity analyses====
====IgG pharmacokinetic parameters====
====IgG pharmacokinetic parameters====
half life 17-19 d, volume of distribution of 5-6 L in the 3 highest dose groups <ref name="First Human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers " />
half life 17-19 d, volume of distribution of 5-6 L in the 3 highest dose groups <ref name="First Human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers " />
 +
====Human anti-chimeric antibody response====
 +
 +
Four(12.5%) of the 32 subjects receiving ch-mAb7F9 were confirmed to have developed a human anti-chimeric antibody response by the end of the study (147 d);however, this response did not appear to be dose related.<ref name="First Human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers " />
== Structural highlights from crystal structure of a high affinity anti-(+)-METH single chain antibody fragment scFv6H4==
== Structural highlights from crystal structure of a high affinity anti-(+)-METH single chain antibody fragment scFv6H4==

Revision as of 21:49, 8 December 2018

Contents

Immunotherapy for treating Methamphetamine Abuse

Introduction

Two major approaches to developing drug-specific immunotherapies: active and passive immunization

Antibody pharmacokinetics, pharmacodynamics and metabolism of therapeutic and diagnostic antibodies

Generation of anti-(+)methamphetamine antibodies during active immunization of rats

Vaccine attenuates methamphetamine-Induced disruptions in thermoregulation and activity in Rats

Vaccination protects rats from methamphetamine-induced impairment of behavioral responding for food

Effects of active anti-methamphetamine vaccination on intravenous self-administration in rats

Combining active immunization with monoclonal antibody therapy To facilitate early initiation of a long-acting anti-methamphetamine antibody response

Development and testing of AAV-delivered single-chain variable fragments for the treatment of methamphetamine abuse

Materials and methods

Synthesis of METH-like haptens

Productions of anti-METH mAb, purification and formulation

Clinical development

Pharmacological effects of two anti-methamphetamine monoclonal antibodies mAb4G9 and mAb7F9

Human-mouse chimeric monoclonal antibody(mAb) Ch-mAb7F9

Preclinical characterization of Ch-mAb7F9 for human use

Cross reactions in vitro ligand binding studies

It did not bind endogenous neurotransmitters or other medications and was not bound by protein C1q, thus it is unlikely to stimulate in vivo complement-dependent cytotoxicity. [1]

Isothermal titration calorimetry potency studies

Binding is efficient. [1]

Pharmacokinetics studies in rats

METH had little effect on ch-mAb7F9 disposition, ch-mAb7F9 substantially altered METH disposition. [1]

Human Study

First Human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers

Serum ch-mAb7F9 concentration

Immunogenicity analyses

IgG pharmacokinetic parameters

half life 17-19 d, volume of distribution of 5-6 L in the 3 highest dose groups [2]

Human anti-chimeric antibody response

Four(12.5%) of the 32 subjects receiving ch-mAb7F9 were confirmed to have developed a human anti-chimeric antibody response by the end of the study (147 d);however, this response did not appear to be dose related.[2]

Structural highlights from crystal structure of a high affinity anti-(+)-METH single chain antibody fragment scFv6H4

Aromatic-Aromatic Interaction: A Mechanism of Protein Structure Stabilization

Hydrophilic interactions of METH

Water molecules in the binding cavity

PDB ID 4lar

Drag the structure with the mouse to rotate
scFv6H4 in complex with amphetamine
Ligands: ,
Gene: IgG (LK3 transgenic mice)
Activity: ,
Related: 3gkz, 4laq, 4las
Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT
Coordinates: save as pdb, mmCIF, xml




References

[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [1] [19] [2] [20] [21]

  1. ↑ 1.0 1.1 1.2 1.3 Stevens MW, Tawney RL, West CM, Kight AD, Henry RL, Owens SM, Gentry WB. Preclinical characterization of an anti-methamphetamine monoclonal antibody for human use. MAbs. 2014 Mar-Apr;6(2):547-55. doi: 10.4161/mabs.27620. Epub 2013 Dec 23. PMID:24492290 doi:http://dx.doi.org/10.4161/mabs.27620
  2. ↑ 2.0 2.1 2.2 Stevens MW, Henry RL, Owens SM, Schutz R, Gentry WB. First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers. MAbs. 2014;6(6):1649-56. doi: 10.4161/19420862.2014.976431. PMID:25484042 doi:http://dx.doi.org/10.4161/19420862.2014.976431
  3. ↑ Burley SK, Petsko GA. Aromatic-aromatic interaction: a mechanism of protein structure stabilization. Science. 1985 Jul 5;229(4708):23-8. PMID:3892686
  4. ↑ Byrnes-Blake KA, Carroll FI, Abraham P, Owens SM. Generation of anti-(+)methamphetamine antibodies is not impeded by (+)methamphetamine administration during active immunization of rats. Int Immunopharmacol. 2001 Feb;1(2):329-38. PMID:11360933
  5. ↑ Peterson EC, Owens SM. Designing immunotherapies to thwart drug abuse. Mol Interv. 2009 Jun;9(3):119-24. doi: 10.1124/mi.9.3.5. PMID:19592672 doi:http://dx.doi.org/10.1124/mi.9.3.5
  6. ↑ Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. 2004 Nov;93(11):2645-68. doi: 10.1002/jps.20178. PMID:15389672 doi:http://dx.doi.org/10.1002/jps.20178
  7. ↑ Kosten T, Owens SM. Immunotherapy for the treatment of drug abuse. Pharmacol Ther. 2005 Oct;108(1):76-85. doi: 10.1016/j.pharmthera.2005.06.009. PMID:16023218 doi:http://dx.doi.org/10.1016/j.pharmthera.2005.06.009
  8. ↑ Hendrickson H, Laurenzana E, Owens SM. Quantitative determination of total methamphetamine and active metabolites in rat tissue by liquid chromatography with tandem mass spectrometric detection. AAPS J. 2006 Nov 22;8(4):E709-17. doi: 10.1208/aapsj080480. PMID:17233534 doi:http://dx.doi.org/10.1208/aapsj080480
  9. ↑ Peterson EC, Gunnell M, Che Y, Goforth RL, Carroll FI, Henry R, Liu H, Owens SM. Using hapten design to discover therapeutic monoclonal antibodies for treating methamphetamine abuse. J Pharmacol Exp Ther. 2007 Jul;322(1):30-9. doi: 10.1124/jpet.106.117150. Epub, 2007 Apr 23. PMID:17452421 doi:http://dx.doi.org/10.1124/jpet.106.117150
  10. ↑ Peterson EC, Laurenzana EM, Atchley WT, Hendrickson HP, Owens SM. Development and preclinical testing of a high-affinity single-chain antibody against (+)-methamphetamine. J Pharmacol Exp Ther. 2008 Apr;325(1):124-33. doi: 10.1124/jpet.107.134395. Epub , 2008 Jan 11. PMID:18192498 doi:http://dx.doi.org/10.1124/jpet.107.134395
  11. ↑ Gentry WB, Ruedi-Bettschen D, Owens SM. Development of active and passive human vaccines to treat methamphetamine addiction. Hum Vaccin. 2009 Apr;5(4):206-13. Epub 2009 Apr 20. PMID:19276653
  12. ↑ Celikel R, Peterson EC, Owens SM, Varughese KI. Crystal structures of a therapeutic single chain antibody in complex with two drugs of abuse - methamphetamine and 3,4 methylenedioxy-N-methylamphetamine. Protein Sci. 2009 Sep 16. PMID:19760665 doi:10.1002/pro.244
  13. ↑ Nanaware-Kharade N, Gonzalez GA 3rd, Lay JO Jr, Hendrickson HP, Peterson EC. Therapeutic anti-methamphetamine antibody fragment-nanoparticle conjugates: synthesis and in vitro characterization. Bioconjug Chem. 2012 Sep 19;23(9):1864-72. doi: 10.1021/bc300204n. Epub 2012 Aug , 28. PMID:22873701 doi:http://dx.doi.org/10.1021/bc300204n
  14. ↑ Miller ML, Moreno AY, Aarde SM, Creehan KM, Vandewater SA, Vaillancourt BD, Wright MJ Jr, Janda KD, Taffe MA. A methamphetamine vaccine attenuates methamphetamine-induced disruptions in thermoregulation and activity in rats. Biol Psychiatry. 2013 Apr 15;73(8):721-8. doi: 10.1016/j.biopsych.2012.09.010., Epub 2012 Oct 23. PMID:23098894 doi:http://dx.doi.org/10.1016/j.biopsych.2012.09.010
  15. ↑ Ruedi-Bettschen D, Wood SL, Gunnell MG, West CM, Pidaparthi RR, Carroll FI, Blough BE, Owens SM. Vaccination protects rats from methamphetamine-induced impairment of behavioral responding for food. Vaccine. 2013 Sep 23;31(41):4596-602. doi: 10.1016/j.vaccine.2013.07.038. Epub, 2013 Jul 29. PMID:23906885 doi:http://dx.doi.org/10.1016/j.vaccine.2013.07.038
  16. ↑ Peterson EC, Celikel R, Gokulan K, Varughese KI. Structural characterization of a therapeutic anti-methamphetamine antibody fragment: oligomerization and binding of active metabolites. PLoS One. 2013 Dec 5;8(12):e82690. doi: 10.1371/journal.pone.0082690. eCollection, 2013. PMID:24349338 doi:http://dx.doi.org/10.1371/journal.pone.0082690
  17. ↑ Thakkar S, Nanaware-Kharade N, Celikel R, Peterson EC, Varughese KI. Affinity improvement of a therapeutic antibody to methamphetamine and amphetamine through structure-based antibody engineering. Sci Rep. 2014 Jan 14;4:3673. doi: 10.1038/srep03673. PMID:24419156 doi:http://dx.doi.org/10.1038/srep03673
  18. ↑ Laurenzana EM, Stevens MW, Frank JC, Hambuchen MD, Hendrickson HP, White SJ, Williams DK, Owens SM, Gentry WB. Pharmacological effects of two anti-methamphetamine monoclonal antibodies. Supporting data for lead candidate selection for clinical development. Hum Vaccin Immunother. 2014;10(9):2638-47. doi: 10.4161/hv.29707. Epub 2014 Nov, 1. PMID:25483484 doi:http://dx.doi.org/10.4161/hv.29707
  19. ↑ Hambuchen MD, Carroll FI, Ruedi-Bettschen D, Hendrickson HP, Hennings LJ, Blough BE, Brieaddy LE, Pidaparthi RR, Owens SM. Combining Active Immunization with Monoclonal Antibody Therapy To Facilitate Early Initiation of a Long-Acting Anti-Methamphetamine Antibody Response. J Med Chem. 2015 Jun 11;58(11):4665-77. doi: 10.1021/acs.jmedchem.5b00220. Epub, 2015 May 22. PMID:25973614 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00220
  20. ↑ Miller ML, Aarde SM, Moreno AY, Creehan KM, Janda KD, Taffe MA. Effects of active anti-methamphetamine vaccination on intravenous self-administration in rats. Drug Alcohol Depend. 2015 Aug 1;153:29-36. doi: 10.1016/j.drugalcdep.2015.06.014., Epub 2015 Jun 19. PMID:26118833 doi:http://dx.doi.org/10.1016/j.drugalcdep.2015.06.014
  21. ↑ Hay CE, Gonzalez GA 3rd, Ewing LE, Reichard EE, Hambuchen MD, Nanaware-Kharade N, Alam S, Bolden CT, Owens SM, Margaritis P, Peterson EC. Development and testing of AAV-delivered single-chain variable fragments for the treatment of methamphetamine abuse. PLoS One. 2018 Jun 29;13(6):e0200060. doi: 10.1371/journal.pone.0200060., eCollection 2018. PMID:29958300 doi:http://dx.doi.org/10.1371/journal.pone.0200060
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