- |||||||||| VRC01 / Acuitas Therap
Journal: Short CDRL1 in intermediate VRC01-like mAbs is not sufficient to overcome key glycan barriers on HIV-1 Env. (Pubmed Central) - Sep 6, 2024
Here we examined whether CDRL1 shortening is a prerequisite for the broadly neutralizing potential of VRC01-class bnAbs, which bind within the CD4 receptor binding site of Env. Our findings indicate that CDRL1 shortening by itself is important but not sufficient for the acquisition of neutralization breadth, and suggest that particular combinations of amino acid mutations, not elicited so far by vaccination, are most likely required for the development of such a feature.
- |||||||||| VRC01 / Acuitas Therap
Enrollment closed, Enrollment change, Trial completion date, Trial primary completion date: Analytical Treatment Interruption (ATI) to Assess the Immune System's Ability to Control HIV in Participants Who Became HIV-infected During the HVTN 703/HPTN 081 AMP Study (clinicaltrials.gov) - Aug 9, 2024
P=N/A, N=13, Active, not recruiting,
Lastly, we show that the ultra-broad N6 bnAb efficiently recognizes different Env conformations and exhibits improved antiviral breadth against VRC01-resistant Envs isolated during the first-in-humans antibody-mediated-prevention trial. Recruiting --> Active, not recruiting | N=39 --> 13 | Trial completion date: Nov 2029 --> Feb 2025 | Trial primary completion date: Nov 2029 --> Feb 2025
- |||||||||| UB-421 IV / United BioPharma
Preclinical, Journal, PD(L)-1 Biomarker, IO biomarker: Ex (Pubmed Central) - Jun 16, 2024
Our data suggest that combination therapy with HIV-specific bNAbs and/or UB-421 in the presence of optimized background therapy could potentially provide sustained virologic suppression in PLWH with MDR HIV. However, this therapeutic strategy needs to be evaluated in human clinical trials.
- |||||||||| VRC01 / Acuitas Therap
Preclinical, Journal: mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models. (Pubmed Central) - May 16, 2024
Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway.
- |||||||||| Plasticity of longitudinal antibody immune responses during antiretroviral treatment-na (Poster board: 017) - May 2, 2024 - Abstract #AIDS2024AIDS_1013;
The embargo on all abstracts, including oral abstract, poster exhibition, e-poster and late breakers, will lift on Tuesday, 23 July 2024, at 10:00 am Central European Summer Time (CEST). If an abstract is part of an official AIDS 2024 press conference that occurs before that time, the embargo on that abstract lifts at the start of the official press conference.
- |||||||||| VRC01 / Acuitas Therap
Human data on CNS penetration by VRC01 in studies from East Africa and Thailand (Room 14a/Channel 9) - May 2, 2024 - Abstract #AIDS2024AIDS_579;
If an abstract is part of an official AIDS 2024 press conference that occurs before that time, the embargo on that abstract lifts at the start of the official press conference. Organized by Division of AIDS Research, National Institute of Mental Health
- |||||||||| VRC01 / Acuitas Therap
Enrollment change, Trial completion date, Trial primary completion date: PET Imaging of Radiolabeled Anti-HIV-1 Envelope Monoclonal Antibody (VRC01) (clinicaltrials.gov) - Aug 14, 2023
P1, N=30, Recruiting,
Trial completion date: Aug 2023 --> Nov 2029 | Trial primary completion date: Aug 2023 --> Nov 2029 N=18 --> 30 | Trial completion date: Oct 2021 --> Jan 2025 | Trial primary completion date: Oct 2021 --> Oct 2024
- |||||||||| VRC01 / Acuitas Therap
Journal: Adjuvants influence the maturation of VRC01-like antibodies during immunization. (Pubmed Central) - Nov 22, 2022
Here, we examined whether and how three adjuvants, Poly(I:C), GLA-LSQ, or Rehydragel, that activate different pathways of the innate immune system, influence the rate and type of somatic mutations accumulated by VRC01-class BCRs that become activated by the germline-targeting 426c.Mod.Core immunogen and the heterologous HxB2.WT.Core booster immunogen. We report that although the adjuvant used had no influence on the durability of plasma antibody responses after the prime, it influenced the plasma VRC01 antibody titers after the boost and the accumulation of somatic mutations on the elicited VRC01 antibodies.
- |||||||||| CAP256V2LS / National Institute of Allergy and Infectious Diseases
Journal: Engineering of HIV-1 neutralizing antibody CAP256V2LS for manufacturability and improved half life. (Pubmed Central) - Oct 27, 2022
The final engineered antibody, CAP256V2LS, retained the extraordinary neutralization potency of the parental antibody, had a favorable pharmacokinetic profile in animal models, and was negative in in vitro assessment of autoreactivity. CAP256V2LS has the requisite potency, developability and suitability for scale-up, allowing its advancement as a clinical candidate.
- |||||||||| VRC01 / Acuitas Therap
Journal: HIV-1 CD4-binding site germline antibody-Env structures inform vaccine design. (Pubmed Central) - Oct 25, 2022
BG24, a VRC01-class broadly neutralizing antibody (bNAb) against HIV-1 Env with relatively few somatic hypermutations (SHMs), represents a promising target for vaccine strategies to elicit CD4-binding site (CD4bs) bNAbs...In addition, biochemical data and cryo-EM structures of BG24 variants bound to Envs with CD4bs glycans present provide insights into N-glycan accommodation, including structural modes of light chain adaptations in the presence of the N276 glycan. Together, these findings reveal Env regions critical for germline antibody recognition and potential sites to alter in immunogen design.
- |||||||||| VRC01 / Acuitas Therap
Journal: Engineering the N-glycosylation pathway of Nicotiana tabacum for molecular pharming using CRISPR/Cas9. (Pubmed Central) - Sep 29, 2022
We confirmed full functional knockout of transformants by immunoblotting of total soluble protein by antibodies recognizing β(1,2)-xylose and core α(1,3)-fucose, mass spectrometry analysis of recombinantly produced VRC01, a broadly neutralizing anti-HIV-1 hIgG1 antibody, and Sanger sequencing of targeted regions of the putative transformants. These data represent an important step toward establishing Nicotiana tabacum as a biologics platform for Global Health.
- |||||||||| VRC01 / Acuitas Therap
Biomarker, Journal: Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition. (Pubmed Central) - Sep 29, 2022
The Antibody Mediated Prevention trials showed that the broadly neutralizing antibody (bnAb) VRC01 prevented acquisition of human immunodeficiency virus-1 (HIV-1) sensitive to VRC01...Based on this result, we suggest that the goal of sustained PT <200 against 90% of circulating viruses can be achieved by promising bnAb regimens engineered for long half-lives. We propose the PT biomarker as a surrogate endpoint for evaluatinon of bnAb regimens, and as a tool for benchmarking candidate bnAb-inducing vaccines.
- |||||||||| Zolinza (vorinostat) / Merck (MSD), Selzentry (maraviroc) / ViiV Healthcare, VRC01 / Acuitas Therap
Journal: Acute HIV-1 infection viremia associate with rebound upon treatment interruption. (Pubmed Central) - Sep 14, 2022
We propose the PT biomarker as a surrogate endpoint for evaluatinon of bnAb regimens, and as a tool for benchmarking candidate bnAb-inducing vaccines. We show that higher viral loads in acute HIV-1 infection were associated with faster viral rebound, demonstrating that the initial stage of HIV-1 infection before ART initiation has a strong impact on viral rebound post-ATI years later.
- |||||||||| VRC01 / Acuitas Therap
Journal, IO biomarker: Association of envelope-specific B-cell differentiation and viral selective pressure signatures in HIV-1 CRF01_AE infection. (Pubmed Central) - Sep 10, 2022
We show that higher viral loads in acute HIV-1 infection were associated with faster viral rebound, demonstrating that the initial stage of HIV-1 infection before ART initiation has a strong impact on viral rebound post-ATI years later. Results revealed the association between circulating Env-specific plasma cell responses and Env polymorphisms, implicating selective pressure on Env by plasma cell-derived antibodies and conversely suggests that Env-specific B-cell induction alone is insufficient for exerting Env selective pressure in HIV infection.
- |||||||||| VRC01 / Acuitas Therap
Journal: A naturally arising broad and potent CD4-binding site antibody with low somatic mutation. (Pubmed Central) - Aug 13, 2022
A 3.8-Å x-ray crystal structure of a BG24-BG505 Env trimer complex revealed conserved contacts at the gp120 interface characteristic of the VRC01-class Abs, despite lacking common CDR3 sequence motifs. The existence of moderately mutated CD4-binding site (CD4bs) bNAbs such as BG24 provides a simpler blueprint for CD4bs antibody induction by a vaccine, raising the prospect that such an induction might be feasible with a germline-targeting approach.
- |||||||||| VRC01 / Acuitas Therap
Journal: Identification of IOMA-class neutralizing antibodies targeting the CD4-binding site on the HIV-1 envelope glycoprotein. (Pubmed Central) - Aug 6, 2022
The VH1-2-derived bNAb IOMA directed to the CD4-binding site of the HIV-1 envelope glycoprotein is of interest because, unlike the better-known VH1-2-derived VRC01-class bNAbs, it does not require a rare short light chain complementarity-determining region 3 (CDRL3)...Cryo-electron microscopy revealed that ACS101 shares interactions with those observed with other VH1-2 and VH1-46-class bNAbs, but exhibits a unique binding mode to residues in loop D. Analysis of longitudinal sequences from the patient suggests that a transmitter/founder-virus lacking the N276 glycan might have initiated the development of these NAbs. Together these data strengthen the rationale for germline-targeting vaccination strategies to induce IOMA-class bNAbs and provide a wealth of sequence and structural information to support such strategies.
- |||||||||| Selzentry (maraviroc) / ViiV Healthcare, VRC01 / Acuitas Therap
Journal: Enhancement of CD4 Binding, Host Cell Entry, and Sensitivity to CD4bs Antibody Inhibition Conferred by a Natural but Rare Polymorphism in the HIV-1 Envelope. (Pubmed Central) - Jul 31, 2022
A rare but natural polymorphism in the HIV-1 envelope (Env) glycoprotein, lysine at position 425 was selected as a mutation conferring resistance to maraviroc (MVC) in vitro...Only K425 was significantly more sensitivity than wild-type N425 A74 to inhibition by the CD4 binding site (bs) compound, BMS-806, the CD4bs antibody, VRC01 and N6, and the single-chain CD4i antibody, SCm9...If CD4bs antibodies did emerge in an infected individual, the K425 HIV-1 may be hypersensitive to inhibition, and thus this K425 virus variant may be removed from the HIV-1 swarm despite its higher replication fitness. Studies are now underway to determine whether addition of the K425 polymorphism into the Envelope-based HIV-1 vaccines could enhance protective immunity.
- |||||||||| VRC01 / Acuitas Therap
Review, Journal: Broadly neutralizing antibodies for treatment and prevention of HIV-1 infection. (Pubmed Central) - Jun 29, 2022
In this review, we discuss the current landscape of HIV-1 bNAbs in clinical development. We also present the current strategies employed to improve the breadth, potency, serum half-life, effector function and administration of these compounds.
- |||||||||| VRC01 / Acuitas Therap
B Cell Depletion Improves Assessment of HIV-1 Broadly Neutralizing Antibody Anti-Viral Efficacy In Vivo (Exhibit and Poster Hall) - Jun 4, 2022 - Abstract #ASMMicrobe2022ASM_Microbe_3270;
This was followed by 3 weekly infusions with 10 mg/kg of VRC01.23LS.J1, a CD4-binding site specific bNAb with improved breadth and potency over VRC01...This slow clearance of the bNAb from the plasma further suggests that this treatment regimen was not impacted by an ADA response. Our results indicate that transient B cell depletion successfully inhibited emergence of ADA and improved the assessment of anti-viral efficacy of a bNAb in a SHIV-infected rhesus macaque model.
- |||||||||| VRC01 / Acuitas Therap
Journal: Broad and ultra-potent cross-clade neutralization of HIV-1 by a vaccine-induced CD4 binding site bovine antibody. (Pubmed Central) - May 26, 2022
MEL-1872 mAb with CDRH3 of 57 amino acids shows more potency (geometric mean half-maximal inhibitory concentration [IC]: 0.009 μg/mL; breadth: 66%) than VRC01 against clade B viruses (29-fold) and than CHO1-31 against tested clade A viruses (21-fold)...Using successive different stable-structured SOSIP trimers in bovines can elicit bNAbs focusing on epitopes ubiquitous across subtypes. Furthermore, the cross-clade selection strategy also results in ultra-potent bNAbs.
- |||||||||| VRC01 / Acuitas Therap
Identification of viral mutations that confer cross resistance to VRC01 antibody in HIV-1 subtype C viruses () - May 12, 2022 - Abstract #AIDS2022AIDS_1155;
Overall, our data supports the concept that some HIV-1 subtype C isolates change critical CD4 binding features to escape VRC01, some causing cross-resistance to other CD4 binding antibodies. The data also promote continued efforts of characterizing VRC01 resistant sites in preparation for future passive immunity trials that include CD4bs antibodies.
- |||||||||| VRC01 / Acuitas Therap
Journal: Multiscale affinity maturation simulations to elicit broadly neutralizing antibodies against HIV. (Pubmed Central) - Apr 27, 2022
The simulation results provide qualitative guidelines for future vaccine design and reveal unique insights into bnAb evolution against the CD4 binding site of HIV. Our model makes possible direct comparisons of simulated BCR populations with results of deep sequencing data, which will be explored in future applications.
- |||||||||| VRC01 / Acuitas Therap
P1 data, Journal: First-in-human immunoPET imaging of HIV-1 infection using Zr-labeled VRC01 broadly neutralizing antibody. (Pubmed Central) - Apr 14, 2022
P1
Importantly, PET tracer uptake in inguinal lymph nodes in viremic and ART-suppressed participants significantly and positively correlates with HIV protein expression measured directly in tissue. Our strategy may allow non-invasive longitudinal characterization of residual HIV infection and lays the framework for the development of immunoPET imaging in a variety of other infectious diseases.
- |||||||||| PGT121 / Gilead, IAVI, VRC01 / Acuitas Therap
Journal: Neutralization Sensitivity of HIV-1 CRF07_BC From an Untreated Patient With a Focus on Evolution Over Time. (Pubmed Central) - Apr 5, 2022
All 24 Env-pseudotyped viruses were resistant to bNAbs 2G12, PGT121, and PGT135...Immune escape mutants resulted in increased resistance to bNAb targeting of different epitopes. Our study identified known mutations F277W in gp41 and previously uncharacterized mutation S465T in V5 which may be associated with increased viral resistance to bNAbs.
- |||||||||| VRC01 / Acuitas Therap
Clinical, Journal: Potent Induction of Envelope-Specific Antibody Responses by Virus-Like Particle (VLP) Immunogens Based on HIV-1 Envelopes from Patients with Early Broadly Neutralizing Responses. (Pubmed Central) - Feb 22, 2022
Both envelopes (Envs) bound to well-characterized broadly neutralizing antibodies (bNAbs), including trimer-specific antibodies (PGT145, VRC01, and 35022)...Here, we show that rabbits immunized with new envelopes (VLP-formulated) from two individuals who demonstrated broadly neutralizing activity very early after infection, induced specific HIV-1 antibodies after a short immunization protocol. This evidence provides the basis for generating protective immune responses with classic vaccination protocols with vaccine prototypes based on HIV envelope sequences from individuals who have developed early broadly neutralizing responses.
- |||||||||| VRC01 / Acuitas Therap
Journal: Internalization of HIV-1 by phagocytes is increased when virions are opsonized with multimeric antibody in the presence of complement. (Pubmed Central) - Feb 19, 2022
In an attempt to improve the ability of antibody to mediate the internalization of HIV-1 virions, we generated multimers of the broadly neutralizing HIV-1-specific monoclonal antibody (MAb) VRC01 using site-directed mutagenesis of the Fc segment...Therefore, antibody multimerization in combination with complement may overcome the limited ability of monomeric antibody to mediate internalization of HIV-1 virions. Our findings may provide a therapeutic approach to clearing virus.
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