Antiviral Activity of Single‐Dose PRO 140, a CCR5 Monoclonal Antibody, in HIV‐Infected Adults

Jacobson, Jeffrey M.; Saag, Michael S.; Thompson, Melanie; Fischl, Margaret A.; Liporace, Ralph; Reichman, Richard C.; Redfield, Robert; Fichtenbaum, Carl J.; Zingman, Barry S.; Patel, Mahesh C.; Murga, Jose D.; Pemrick, Suzanne M.; D’Ambrosio, Paul; Michael, Marti; Kröger, Hans; Ly, Hieu; Rotshteyn, Yakov; Buice, Robert G.; Morris, Stephen A.; Stavola, Joseph J.; Maddon, Paul J.; Kremer, Alton B.; Olson, William C.

doi:10.1086/592169

Cited by 101 publications

(88 citation statements)

References 38 publications

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“…Moreover, a host of other small-molecule CCR5 antagonists have been advanced into development (Jacobson et al, 2008;Westby and van der Ryst, 2010). In contrast, the alternative strategy based on the use of CCR5 agonists has garnered far less attention.…”

Section: Discussionmentioning

confidence: 99%

“…The successful launch of maraviroc (Dorr et al, 2005), a CCR5 antagonist from Pfizer (Sandwich, Kent, UK), has validated this G protein-coupled receptor as a target for the treatment of HIV-1 infections. In addition to maraviroc, several other CCR5 antagonists or monoclonal antibody inhibitors also have been optimized, some of which have entered clinical development (Jacobson et al, 2008;Westby and van der Ryst, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Agonist-Induced Internalization of CC Chemokine Receptor 5 as a Mechanism to Inhibit HIV Replication

Ferain

Hoveyda²,

Ooms³

et al. 2011

J Pharmacol Exp Ther

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The chemokine G protein-coupled receptor CC chemokine receptor 5 (CCR5) is used as an entry gate by CCR5-tropic and dual-or CCR5/CXC chemokine receptor 4-tropic strains of HIV to enter the human host cells. Thus, CCR5 antagonists (i.e., maraviroc) have been proven to be clinically effective by preventing the interaction between viral glycoprotein 120 and CCR5 and thus impeding viral entry into host cells. However, the emergence of HIV strains resistant to CCR5 antagonists has been reported in vitro and in vivo, where the virus has adapted to enter the cells via antagonist-bound CCR5. An alternative strategy that should obviate this mode of viral resistance would entail the ablation of the CCR5 portal for HIV entry from the cell surface through agonist-induced receptor internalization. Although this protective effect has been demonstrated clearly with natural CCR5 ligands, the chemoattractant properties of these chemokines have precluded them from further consideration in terms of drug development. Thus, we sought to explore the possibility of developing novel small molecules and selective CCR5 agonists devoid of eliciting chemotaxis. Indeed, the CCR5 agonists described herein were found to induce profound downmodulation of CCR5 (and not CXC chemokine receptor 4) from the cell surface and its sustained sequestration in the intracellular compartment without inducing chemotaxis in vitro. The bioactivity profile of these novel CCR5 agonists is exemplified by the compound (R)-2-(4-cyanophenyl)-N-(1-(1-(N,1-diphenylmethylsulfonamido)propan-2-yl)piperidin-4-yl)acetamide ) that potently inhibits HIV-1 infection in human peripheral blood mononuclear cells and macrophages in vitro with potencies comparable to that of maraviroc and moreover demonstrates full activity against a maraviroc-resistant HIV-1 RU570 strain.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Agonist-Induced Internalization of CC Chemokine Receptor 5 as a Mechanism to Inhibit HIV Replication

Ferain

Hoveyda²,

Ooms³

et al. 2011

J Pharmacol Exp Ther

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“…tor/attachment inhibitors PRO 140, PRO 542, and anti-CD81 for HIV (24,25,30,58) and hepatitis C virus (39), respectively. Unfortunately, the identification of viral receptors as antiviral targets can be problematic, and many viruses do not share common receptors.…”

mentioning

confidence: 99%

Orthobunyavirus Entry into Neurons and Other Mammalian Cells Occurs via Clathrin-Mediated Endocytosis and Requires Trafficking into Early Endosomes

Hollidge

Nedelsky

Salzano

et al. 2012

J Virol

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c La Crosse virus (LACV) is a leading cause of pediatric encephalitis and aseptic meningitis in the midwestern and southern United States, where it is considered an emerging human pathogen. No specific therapies or vaccines are available for LACV or any other orthobunyaviruses. Inhibition of LACV entry into cells is a potential target for therapeutic intervention, but this approach is limited by our current knowledge of the entry process. Here, we determined that clathrin-mediated endocytosis is the primary mechanism of orthobunyavirus entry and identified key cellular factors in this process. First, we demonstrated that LACV colocalized with clathrin shortly after infection in HeLa cells; we then confirmed the functional requirement of dynaminand clathrin-mediated endocytosis for orthobunyavirus entry using several independent assays and, importantly, extended these findings to primary neuronal cultures. We also determined that macropinocytosis and caveolar endocytosis, both established routes of virus entry, are not critical for cellular entry of LACV. Moreover, we demonstrated that LACV infection is dependent on Rab5, which plays an important regulatory role in early endosomes, but not on Rab7, which is associated with late endosomes. These findings provide the first description of bunyavirus entry into cells of the central nervous system, where infection can cause severe neurological disease, and will aid in the design and development of antivirals and therapeutics that may be useful in the treatment of LACV and, more broadly, arboviral infections of the central nervous system.

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“…Therefore, antibodies which bind viral entry receptors may provide an attractive addition to standard HIV therapy. Current therapeutics under development, such as the anti-CD4 antibody ibalizumab (formerly known as TNX-355) (10,12,14,22) and the anti-CCR5 antibodies PRO 140 and HGS004 (14,23), have shown efficacy against viral infections in vitro and in clinical trials (11,15,16,24,25). We recently described two CCR5 antibodies with high antiviral activity in vitro (16,18,40): RoAb13, which binds to the NTD of CCR5, and MAb3952, which recognizes extracellular domain 2 (ECL-2) of CCR5 (16).…”

mentioning

confidence: 99%

Development of Tetravalent, Bispecific CCR5 Antibodies with Antiviral Activity against CCR5 Monoclonal Antibody-Resistant HIV-1 Strains

Schanzer

Jekle

Nezu

et al. 2011

Antimicrob Agents Chemother

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In this study, we describe novel tetravalent, bispecific antibody derivatives that bind two different epitopes on the HIV coreceptor CCR5. The basic protein formats that we applied were derived from Morrison-type bispecific antibodies: whole IgGs to which we connected single-chain antibodies (scFvs) via (Gly 4 Ser) n sequences at either the C or N terminus of the light chain or heavy chain. By design optimization, including disulfide stabilization of scFvs or introduction of 30-amino-acid linkers, stable molecules could be obtained in amounts that were within the same range as or no less than 4-fold lower than those observed with monoclonal antibodies in transient expression assays. In contrast to monospecific CCR5 antibodies, bispecific antibody derivatives block two alternative docking sites of CCR5-tropic HIV strains on the CCR5 coreceptor. Consequently, these molecules showed 18-to 57-fold increased antiviral activities compared to the parent antibodies. Most importantly, one prototypic tetravalent CCR5 antibody had antiviral activity against virus strains resistant to the single parental antibodies. In summary, physical linkage of two CCR5 antibodies targeting different epitopes on the HIV coreceptor CCR5 resulted in tetravalent, bispecific antibodies with enhanced antiviral potency against wild-type and CCR5 antibodyresistant HIV-1 strains.

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Antiviral Activity of Single‐Dose PRO 140, a CCR5 Monoclonal Antibody, in HIV‐Infected Adults

Abstract: ISRCTN Register: ISRCTN45537485 .

Cited by 101 publications

References 38 publications

Agonist-Induced Internalization of CC Chemokine Receptor 5 as a Mechanism to Inhibit HIV Replication

Agonist-Induced Internalization of CC Chemokine Receptor 5 as a Mechanism to Inhibit HIV Replication

Orthobunyavirus Entry into Neurons and Other Mammalian Cells Occurs via Clathrin-Mediated Endocytosis and Requires Trafficking into Early Endosomes

Development of Tetravalent, Bispecific CCR5 Antibodies with Antiviral Activity against CCR5 Monoclonal Antibody-Resistant HIV-1 Strains

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