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POTENT ANTIVIRAL ACTIVITY OF TRISPECIFIC BROADLY NEUTRALIZING HIV ANTIBODIES
Amarendra Pegu1, Ling Xu2, Megan Demouth1, Cassandra Almasri1, Eun S. Yang1, Jason M. Hataye1, Mangaiarkarasi Asokan1, Wanwisa Promsote1, Ronnie R. Wei2, Dana M. Lord2, Ercole Rao2, Jochen Beninga2, Zhi-yong Yang2, John R. Mascola1, Gary Nabel2
1Vaccine Research Center, NIAID, Bethesda, MD, USA,2Sanofi, Cambridge, MA, USA
Broadly neutralizing antibodies (bnAbs) against HIV-1 have been suggested as a complementary immunotherapy to current combination small molecule anti-retroviral therapies (cART) for treatment of HIV-1 infection. Due to their monospecific nature, use of single bnAbs leads to rapid selection for escape variants in most HIV-1 infected patients and therefore use of a combination of 2 or more bnAbs is desirable to maintain durable suppression of HIV-1 replication.
We engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: 1) the CD4 binding site, 2) the membrane proximal external region (MPER) and 3) the V1V2 glycan site. Prior studies demonstrated improved neutralization compared to parental bnAbs. These trispecific Abs have an intact IgG1 backbone and were assessed for Fc effector function and ability to suppress virus replication from activated HIV-1 infected donor T cells. One of the trispecific Abs was administered to viremic simian-human immunodeficiency virus (SHIV)-infected rhesus macaques to assess inhibition of viral replication.
Each of the three combining sites of the trispecific Abs were actively bound with high affinity binding to the HIV envelope glycoprotein. In addition, trispecific Abs retained binding to Fcγ receptors via their Fc region and mediated antibody dependent cellular cytotoxicity (ADCC). In cultures of activated CD4+ T cells from HIV-1 infected patients, trispecific Abs durably suppressed viral replication compared to individual parental bnAbs. In viremic SHIV-infected macaques, treatment with trispecific Abs reduced plasma viremia up to 1000-fold that was maintained until the plasma trispecific Ab levels dropped below a value that was greater than 5-fold its IC80 titer against the SHIV.
Trispecific HIV antibodies demonstrate potent neutralization and ADCC in vitro, and mediate antiviral activity in vivo. Thus, trispecific Abs provide an attractive single immunotherapeutic protein for treatment of HIV-1 infection.