CIS43LS

Associated long-acting platforms

Monoclonal Antibody

Administration route

Subcutaneous, Intravenous

Therapeutic area(s)

Use case(s)

Use of drug

Dosage

Drug information

Delivery device(s)

No delivery device

Scale-up prospects

Manufacturing requirements and production scale-up for therapeutic monoclonal antibodies (mAbs) is primarily focused on pharmacokinetic suitability, formulation stability and overall maintenance of product quality. In addition, industrial bioprocessing steps can introduce further challenges regarding mAb formulation viscosity and aggregation propensity.

Tentative equipment list for manufacturing

Industrial bioreactor vessel with a production volume capacity of between 5-25kL. Continuous disc stack centrifuges for bioreactor harvesting with subsequent membrane and depth filtration for supernatant clarification. Recombinant protein-A chromatography or other suitable affinity capture apparatus followed by two chromatographic polishing steps such as cation- and anion-exchange. Ultrafiltration membrane system to concentrate and formulate the final product.

Manufacturing

MAbs are highly dependent on their structural, chemical and conformational stability for biological activity. Chemical degradation of mAbs during manufacture can lead to the generation of product variants and complex impurity profiles resulting from a wide range of processes, including: N-linked glycosylation, isomerisation, fragmentation, deamidation, oxidation and C-terminal lysine clipping. Additionally prior to packaging, the final product requires close monitoring for the presence of residual contaminants such as endotoxins and pro-inflammatory peptidoglycans.

Specific analytical instrument required for characterization of formulation

Formulation characterisation steps for therapeutic mAb products include (but are not limited to): (1) Identification of post-translational modifications using ion-exchange chromatography and capillary isoelectric focusing, (2) Measurement of concentration dependent aggregation rates via thermal differential scanning calorimetry, sub-visible particle quantitation and size-exclusion chromatography, and (3) Antibody clipping and fragmentation detection by capillary electrophoresis.

VRC 612

Identifier

NCT04206332

Link

https://www.clinicaltrials.gov/study/NCT04206332

Phase

Phase I

Status

Completed

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

More details

Not provided

Purpose

Evaluate the protective efficacy, tolerability, safety and dose of the anti-malarial human monoclonal antibody CIS43LS (VRC-MALMAB0100-00-AB).

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2020-01-07

Anticipated Date of Last Follow-up
Not provided

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2022-02-28

Actual Completion Date
2022-02-28

Studied populations

Age Cohort

• Adults

Genders

• All

Accepts pregnant individuals
No

Accepts lactating individuals
No

Accepts healthy individuals
Yes

Comments about the studied populations

Study participants aged between 18 to 50 years and in good general health without clinically significant medical history. Exclusion criteria includes previous receipt of a malaria vaccine.

Health status

Study type

Interventional (clinical trial)

Enrollment

71

Allocation

Non-randomized

Intervention model

Sequential assignment

Intervention model description

Not provided

Masking

Open label

Masking description

None (Open Label)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

PrEP

Key results

2020/32/CE/FMOS/FAPH

Identifier

NCT04329104

Link

https://www.clinicaltrials.gov/study/NCT04329104

Phase

Phase II

Status

Completed

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

More details

Not provided

Purpose

Evaluate the safety, tolerability, and efficacy of VRC MALMAB0100-00-AB (CIS43LS), a human monoclonal antibody, against naturally occurring Plasmodium falciparum (Pf) infection.

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2021-02-15

Anticipated Date of Last Follow-up
Not provided

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2022-01-26

Actual Completion Date
2023-07-05

Studied populations

Age Cohort

• Adults

Genders

• All

Accepts pregnant individuals
No

Accepts lactating individuals
No

Accepts healthy individuals
Yes

Comments about the studied populations

Participants aged ≥18 and ≤55 years and in good general health and without clinically significant medical history.

Health status

Study type

Interventional (clinical trial)

Enrollment

348

Allocation

Randomized

Intervention model

Sequential assignment

Intervention model description

Not provided

Masking

Double-blind masking

Masking description

Double (Participant, Investigator)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

PrEP

Key results

Proprietary excipients used

Not provided

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

Not provided

Residual solvents used

Not provided

There are either no relevant patents or these were not yet submitted to LAPaL

Publications

Kisalu NK, Pereira LD, Ernste K, Flores-Garcia Y, Idris AH, Asokan M, Dillon M, MacDonald S, Shi W, Chen X, Pegu A, Schön A, Zavala F, Balazs AB, Francica JR, Seder RA. Enhancing durability of CIS43 monoclonal antibody by Fc mutation or AAV delivery for malaria prevention. JCI Insight. 2021 Feb 8;6(3):e143958. DOI: 10.1172/jci.insight.143958. PMID: 33332286; PMCID: PMC7934869.

CIS43 is a potent neutralizing human mAb that targets a highly conserved “junctional” epitope in the Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP). Enhancing the durability of CIS43 in vivo will be important for clinical translation. Here, 2 approaches were used to improve the durability of CIS43 in vivo while maintaining potent neutralization. First, the Fc domain was modified with the LS mutations (CIS43LS) to increase CIS43 binding affinity for the neonatal Fc receptor (FcRn). CIS43LS and CIS43 showed comparable in vivo protective efficacy. CIS43LS had 9- to 13-fold increased binding affinity for human (6.2 nM versus 54.2 nM) and rhesus (25.1 nM versus 325.8 nM) FcRn at endosomal pH 6.0 compared with CIS43. Importantly, the half-life of CIS43LS in rhesus macaques increased from 22 days to 39 days compared with CIS43. The second approach for sustaining antibody levels of CIS43 in vivo is through adeno-associated virus (AAV) expression. Mice administered once with AAV-expressing CIS43 had sustained antibody levels of approximately 300 μg/mL and mediated protection against sequential malaria challenges up to 36 weeks. Based on these data, CIS43LS has advanced to phase I clinical trials, and AAV delivery provides a potential next-generation approach for malaria prevention.

Additional documents

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Useful links

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