VRC07-523LS (mAb) (TMB-380)

Drug information

Drug's link(s)

https://clinicalinfo.hiv.gov/en/drugs/vrc07-523ls/patient

Generic name

VRS07-523LS; VRC-HIVMAB075-00-AB; TMB-380

Brand names

Not applicable (investigational; no brand name assigned)

Compound type

Biotherapeutic

Drug class/category

mAb (Monoclonal antibody) — bNAb targeting gp120 on HIV-1 virus envelope

Lifecycle status

Active / In Development (Phase 1/2/3)

Summary

VRC07-523LS (VRC-HIVMAB075-00-AB; TMB-380) is a broadly neutralizing antibody (bNAb) engineered to target the CD4 binding site on HIV’s envelope protein gp120. It is a modified version of VRC01, with an LS mutation that extends its half-life, allowing less frequent dosing. Administered via IV, IM, SC, it has shown safety and tolerability in clinical trials. TaiMed develops TMB-380 as part of the antibody-only TMB-365/TMB-380 regimen at 4,800 mg IV every 8 weeks. VRC07-523LS is an engineered VRC01-class antibody with the LS Fc modification, neutralising 96% of strains at IC50 below 50 microgram/mL and 92% below 1 microgram/mL, with 5- to 8-fold greater potency than VRC01.

Approval status

Not yet approved

Regulatory authorities

Not yet approved

Therapeutic area(s)

Use case(s)

Pre-Exposure Prophylaxis (PrEP)
Treatment

Administration route

Intravenous, Subcutaneous, Intramuscular

Associated long-acting platforms

Monoclonal antibodies and antibody drug conjugates

Use of drug

Ease of administration

Administered by a nurse
Administered by a specialty health worker

Frequency of administration

Every 3 months
Every 6 months
Every 2 months
Every 4 months

User acceptance

To be determined. In CAPRISA 012A (with PGT121), 86.7% of African women found two to three subcutaneous administrations per year acceptable for HIV prevention. Generally safe and well tolerated across phase 1 studies.

Dosage

Available dose and strength

Investigational: weight-based 5 to 40 mg/kg (5 mg/kg; 20mg/kg; 40mg/kg) IV or SC; fixed doses 400 mg to 3,200 mg IV; 1.2 g SC (CAPRISA 012C); 2,400, 3,200 and 4,800 mg IV (TaiMed programme).

Maximum dose

40 mg/kg IV (phase 1); 4,800 mg IV fixed dose (as TMB-380)

Recommended dosing regimen

No approved regimen. Examples: with CAB-LA (ACTG A5357); 1.2 g SC every 6 months with CAP256V2LS (CAPRISA 012C part B); 4,800 mg IV every 8 weeks with TMB-365 4,800 mg IV. ; VRC07-523LS 20 mg/kg IV Q12W- 3 doses ; VRC07-523LS 5 mg/kg SC Q12W- 3 doses

Additional comments

Not provided

Dosage link(s)

Not provided

Related entries

Compounds

Compare

Main compound
VRC01 (mAb)

Related compounds
VRC01.23LS (mAb)
VRC07-523LS (mAb) (TMB-380)

Additional information

Not provided

Developer(s)

Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID)

Originator

United States of America

Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID)

The National Institute of Allergy and Infectious Diseases (NIAID) is a key institute within the National Institutes of Health (NIH) dedicated to advancing research on infectious, immunologic, and allergic diseases. Established over 60 years ago, NIAID conducts both basic and applied research aimed at improving understanding, diagnosis, treatment, and prevention of these diseases.

Originator

TaiMed Biologics

Drug structure

Scale-up and manufacturing prospects

Scale-up prospects

Not provided

Tentative equipment list for manufacturing

Bioreactors, incubators, filtration units, lyophilizers, and formulation vessels.

Manufacturing

VRC07-5LS is a monoclonal antibody, and its production involves several key steps: VRC07-523LS is produced in a Chinese Hamster Ovary (CHO) DG44 cell line. Further information is not disclosed yet.

Specific analytical instrument required for characterization of formulation

1. Bio-Plex Instrument (Bio-Rad) 2. Beckman Biomek Automation Platform 3. Surface-Plasmon-Resonance-(SPR)-Systeme 4. Dynamic Light Scattering, 5. Differential Scanning Calorimetry 6. Circular dichroism and isothermal chemical denaturation

Excipients & delivery device(s)

Proprietary excipients used

No proprietary excipient used

Novel excipients or existing excipients at a concentration above Inactive Ingredient Database (IID) for the specified route of administration

No novel excipient or existing excipient used

Residual solvents used

No residual solvent used

Delivery device(s)

No delivery device

Safety, Efficacy and Evidence Summary

Safety

Not provided

Efficacy

Not provided

Evidence Summary

Not provided

References and relevant studies

Not provided

Antibody characteristics

Molecular identity

Antibody format

IgG monoclonal

Isotype and subclass

IgG1

Light chain

Kappa

Origin

Human (donor-derived)

Expression system

CHO DG44

Molecular weight

Not provided

Comment

The VRC07 heavy chain was identified from antibody transcripts of donor 45 (same donor from whom VRC01 was isolated). It is approximately 90% nucleotide-identical to the VRC01 heavy chain, differing at 15 amino acid positions with a four-amino-acid insertion in CDRH3, and was paired with the VRC01 light chain to create VRC07.

Epitope and engineering

Lineage / class

VRC01-class

Epitope class

CD4-binding site

Key contact residues

Not provided

Fc modification

LS (M428L/N434S)

Half-life extension factor

2.3

Comment

The CD4 binding site is the most conserved of the major bNAb epitopes, which is why this class achieves the greatest breadth: 96% of a 179-virus panel at IC50 below 50 microgram/mL. VRC07-523 was engineered specifically to raise potency over VRC01, whose AMP trial result established that breadth without sufficient potency does not deliver population-level prevention efficacy.

Delivery

Dose mass per person-year

Not provided

Maximum formulated concentration

Not provided

Injection volume per dose

Not provided

Number of injection sites per dose

Not provided

Hyaluronidase co-formulation

Comment

One injeciton for the 80 to 120 mg infant doses. For adults the VRC 605 protocol specified approximately 2.5 mL per injection site with up to four sites if clinically necessary, preferred site the abdomen with upper arm or thigh as alternatives and sites at least 2 inches apart. Fixed adult SC doses of 1.2 to 1.4 g exceed that four-site envelope at this concentration.

Neutralisation and resistance profile

Assay context

Neutralisation assay

TZM-bl Env-pseudovirus

Virus panel name

Not provided

Panel size

179

Censoring convention

Not provided

Data source

Not provided

Potency and breadth

Potency calculation convention

Not provided

Number of viruses neutralised below threshold

Not provided

IC50, geometric mean

Not provided

IC50, median

Not provided

IC50 range

Not provided

IC80, geometric mean

Not provided

Breadth at IC50 < 1 µg/mL

Not provided

Breadth at IC50 < 10 µg/mL

Not provided

Breadth at IC50 < 50 µg/mL

Not provided

Breadth at IC80 < 1 µg/mL

Not provided

Value type

Not provided

Comment

VRC07-523 neutralised 171 of 179 viruses (96%) at IC50 below 50 microgram/mL and 165 of 179 (92%) below 1 microgram/mL, with IC50 geometric means of 0.039 microgram/mL on neutralised viruses and 0.055 on all viruses. Equivalent VRC01 figures on the same panel were 89% and 77% with IC50 geometric means of 0.221 and 0.434, so the engineered molecule is 5.6- to 7.9-fold more potent.

Resistance and sensitivity

Baseline sensitivity testing required

Under evaluation

Signature resistance mutations

Loop D is the principal escape hotspot for the VRC01 class, at positions 276, 279 and 280, with mutations N276T/I, D279G/Y/A and N280D. The N197 glycan and the beta23-V5 region also implicated

Genotypic resistance prediction feasible

Partially

Sequence region required for prediction

Not provided

Emergent resistance on therapy

Not reported for VRC07-523LS itself.

Transmitted/founder virus sensitivity

Transmitted/founder (T/F) virus sensitivity

Not provided

T/F panel description

Not provided

Reference

Not provided

Clade coverage

Not provided

Description

VRC07-523LS antibody

Brief description

Antibodies and antigen binding fragments that specifically bind to HIV-1 Env and neutralize HIV-1 are disclosed. Nucleic acids encoding these antibodies, vectors and host cells are also provided. Methods for detecting HIV-1 using these antibodies are disclosed. In addition, the use of these antibodies, antigen binding fragment, nucleic acids and vectors to prevent and/or treat an HIV-1 infection is disclosed.

Representative patent

WO2019165122