Recombinant CD4‐IgG2 in Human Immunodeficiency Virus Type 1–Infected Children: Phase 1/2 Study

Shearer, William T.; Israel, Robert J.; Starr, Stuart E.; Fletcher, Courtney V.; Wara, Diane W.; Rathore, Mobeen H.; Church, Joseph A.; Deville, Jaime G.; Fenton, Terence; Graham, Bobbie; Samson, Pearl; Staprans, Silvija I.; McNamara, James; Moye, John; Maddon, Paul J.; Olson, William C.

doi:10.1086/317622

Cited by 78 publications

(54 citation statements)

References 11 publications

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“…Although sCD4 demonstrated efficacy against many laboratory strains, it exhibited poor activity against primary isolates (31), which may have contributed to disappointing results in clinical trials (31,32). PRO-542 (a CD4-IgG fusion protein) was shown to be effective in neutralizing many clinical HIV-1 strains in culture (15,33) and is efficacious in the clinics (16,34). However, this recombinant fusion protein requires i.v.…”

Section: Discussionmentioning

confidence: 99%

“…Structural information of the HIV-1 envelope has been provided by x-ray crystallography studies of the gp120 core protein complexed with a two-domain fragment of CD4 and a monoclonal antibody (13,14). Proof of concept for entry targets has been obtained in clinical trials using the attachment inhibitor PRO542 (a CD4-IgG fusion protein) (15,16), the CCR5 coreceptor antagonist SCH-C, ¶ and the fusion inhibitor enfuvirtide (17)(18)(19). In this study, a small molecule inhibitor of viral entry, BMS-378806, is characterized with regards to its antiviral activity, inhibition mechanism, resistance profile, and preliminary pharmacokinetic properties.…”

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confidence: 99%

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A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding

Lin

Blair

Wang

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

341

302

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding

Lin

Blair

Wang

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

341

302

View full text Add to dashboard Cite

“…Co-administration of PRO-542 and T-20 contribute to synergistic inhibition against diverse HIV-1 subtypes . Clinical phase 1/2 studies reveal that PRO-542 is well tolerated by both HIV-1 infected adults and children, and confers sustained reduction in HIV-1 load (Shearer et al, 2000;Jacobson et al, 2004). These findings support the development of PRO-542 as an approved medication for clinical use.…”

Section: Synthesized Peptides and Polymersmentioning

confidence: 58%

Closing the door to human immunodeficiency virus

2013

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The pandemic of human immunodeficiency virus type one (HIV-1), the major etiologic agent of acquired immunodeficiency disease (AIDS), has led to over 33 million people living with the virus, among which 18 million are women and children. Until now, there is neither an effective vaccine nor a therapeutic cure despite over 30 years of efforts. Although the Thai RV144 vaccine trial has demonstrated an efficacy of 31.2%, an effective vaccine will likely rely on a breakthrough discovery of immunogens to elicit broadly reactive neutralizing antibodies, which may take years to achieve. Therefore, there is an urgency of exploring other prophylactic strategies. Recently, antiretroviral treatment as prevention is an exciting area of progress in HIV-1 research. Although effective, the implementation of such strategy faces great financial, political and social challenges in heavily affected regions such as developing countries where drug resistant viruses have already been found with growing incidence. Activating latently infected cells for therapeutic cure is another area of challenge. Since it is greatly difficult to eradicate HIV-1 after the establishment of viral latency, it is necessary to investigate strategies that may close the door to HIV-1. Here, we review studies on non-vaccine strategies in targeting viral entry, which may have critical implications for HIV-1 prevention.

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“…Alexa Fluor 488-conjugated RAC18 MAb to the ricin A chain was prepared as previously described (51). Soluble CD4-IgG2 (Pro542) was from Progenics Pharmaceuticals, Tarrytown NY (52,53). Goat anti-human or anti-mouse IgG (heavy and light chains) was conjugated to either alkaline phosphatase (AP) or fluorescein isothiocyanate (FITC) (Life Technologies, Inc.).…”

Section: Methodsmentioning

confidence: 99%

Design andIn VivoCharacterization of Immunoconjugates Targeting HIV gp160

Pincus

Song

Maresh

et al. 2017

J Virol

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The envelope (Env) glycoprotein of HIV is expressed on the surface of productively infected cells and can be used as a target for cytotoxic immunoconjugates (ICs), in which cell-killing moieties, including toxins, drugs, or radionuclides, are chemically or genetically linked to monoclonal antibodies (MAbs) or other targeting ligands. Such ICs could be used to eliminate persistent reservoirs of HIV infection. We have found that MAbs which bind to the external loop of gp41, e.g., MAb 7B2, make highly effective ICs, particularly when used in combination with soluble CD4. We evaluated the toxicity, immunogenicity, and efficacy of the ICs targeted with 7B2 in mice and in simian-human immunodeficiency virus-infected macaques. In the macaques, we tested immunotoxins (ITs), consisting of protein toxins bound to the targeting agent. ITs were well tolerated and initially efficacious but were ultimately limited by their immunogenicity. In an effort to decrease immunogenicity, we tested different toxic moieties, including recombinant toxins, cytotoxic drugs, and tubulin inhibitors. ICs containing deglycosylated ricin A chain prepared from ricin toxin extracted from castor beans were the most effective in killing HIVinfected cells. Having identified immunogenicity as a major concern, we show that conjugation of IT to polyethylene glycol limits immunogenicity. These studies demonstrate that cytotoxic ICs can target virus-infected cells in vivo but also highlight potential problems to be addressed. IMPORTANCE It is not yet possible to cure HIV infection. Even after years of fully effective antiviral therapy, a persistent reservoir of virus-infected cells remains. Here we propose that a targeted conjugate consisting of an anti-HIV antibody bound to a toxic moiety could function to kill the HIV-infected cells that constitute this reservoir. We tested this approach in HIV-infected cells grown in the lab and in animal infections. Our studies demonstrated that these immunoconjugates are effective both in vitro and in test animals. In particular, ITs constructed with the deglycosylated A chain prepared from native ricin were the most effective in killing cells, but their utility was blunted because they provoked immune reactions that interfered with the therapeutic effects. We then demonstrated that coating of the ITs with polyethylene glycol minimized the immunogenicity, as has been demonstrated with other protein therapies.

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Recombinant CD4‐IgG2 in Human Immunodeficiency Virus Type 1–Infected Children: Phase 1/2 Study

Cited by 78 publications

References 11 publications

A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding

A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding

Closing the door to human immunodeficiency virus

Design andIn VivoCharacterization of Immunoconjugates Targeting HIV gp160

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