L9LS

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

L9LS has been manufactured as a clinical trial product by Leidos Biomedical Research following good manufacturing practices and vialled at a concentration of 150mg/mL within a buffered solution. General manufacturing requirements and production scale-up for therapeutic monoclonal antibody (mAb) products is primarily focused on pharmacokinetic suitability, formulation stability and the overall maintenance of product quality. Industrial bioprocessing steps can also potentially introduce additional 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.

2022/34/CE/USTTB

Identifier

NCT05304611

Link

https://www.clinicaltrials.gov/study/NCT05304611

Phase

Phase II

Status

Completed

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

More details

Not provided

Purpose

Evaluate the safety and tolerability of L9LS in healthy Malian adults and children, in addition to assessing its protective efficacy during a 7-month malaria season in healthy Malian children.

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2022-03-18

Anticipated Date of Last Follow-up
2024-06-12

Estimated Primary Completion Date
Not provided

Estimated Completion Date
2024-04-01

Actual Primary Completion Date
2023-01-31

Actual Completion Date
2024-04-20

Studied populations

Age Cohort

• Children
• Adults

Genders

• All

Accepts pregnant individuals
No

Accepts lactating individuals
Unspecified

Accepts healthy individuals
Yes

Comments about the studied populations

Adults: Aged ≥18 years. Children: Aged ≥6 years and <11 years. Participants are required to be in good general health and without clinically significant medical history. Any participants that have been previously in receipt of an investigational malaria vaccine or monoclonal antibody in the last 5 years are excluded.

Health status

Study type

Interventional (clinical trial)

Enrollment

365

Allocation

Randomized

Intervention model

Sequential assignment

Intervention model description

Not provided

Masking

Triple-blind masking

Masking description

Triple (Participant, Care Provider, Investigator)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

PrEP

Key results

2023/109/CE/USTTB

Identifier

NCT05816330

Link

https://www.clinicaltrials.gov/study/NCT05816330

Phase

Phase II

Status

Completed

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

More details

Not provided

Purpose

Evaluate the safety and tolerability of a one time subcutaneous (SC) administration of L9LS, as well its protective efficacy against naturally occurring Pf infection over a 6-month malaria season.

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2023-05-25

Anticipated Date of Last Follow-up
2024-04-16

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2024-02-11

Actual Completion Date
2024-02-11

Studied populations

Age Cohort

• Adults

Genders

• All

Accepts pregnant individuals
No

Accepts lactating individuals
No

Accepts healthy individuals
Yes

Comments about the studied populations

Females aged ≥18 and ≤49 years and weighing ≥ 45.0 and ≤ 90.0 kg. Males aged ≥18 and ≤55 years and weighing ≥ 50.0 and ≤ 100.0 kg. Exclusion criteria includes prior receipt of an investigational malaria vaccine or monoclonal antibody within the last 5 years.

Health status

Study type

Interventional (clinical trial)

Enrollment

288

Allocation

Randomized

Intervention model

Sequential assignment

Intervention model description

Not provided

Masking

Triple-blind masking

Masking description

Triple (Participant, Care Provider, Investigator)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

PrEP

Key results

VRC 614

Identifier

NCT05019729

Link

https://www.clinicaltrials.gov/study/NCT05019729

Phase

Phase I

Status

Completed

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

More details

Not provided

Purpose

Evaluate the safety, tolerability, pharmacokinetics and protective efficacy of the anti-malaria human monoclonal antibody, VRC-MALMAB0114-00-AB (L9LS).

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2021-09-13

Anticipated Date of Last Follow-up
2024-07-19

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2022-09-19

Actual Completion Date
2022-09-19

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 18-50 years.

Health status

Study type

Interventional (clinical trial)

Enrollment

32

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

SERU 4413

Identifier

NCT05400655

Link

https://www.clinicaltrials.gov/study/NCT05400655

Phase

Phase II

Status

Completed

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

More details

Not provided

Purpose

Evaluate the safety and tolerability of L9LS in healthy Kenyan children; Determining the protective efficacy of one or two doses of L9LS against P. falciparum infection in a high transmission setting.

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2022-09-14

Anticipated Date of Last Follow-up
2024-09-11

Estimated Primary Completion Date
2024-06-30

Estimated Completion Date
2024-06-30

Actual Primary Completion Date
2024-06-02

Actual Completion Date
2024-06-02

Studied populations

Age Cohort

• Children

Genders

• All

Accepts pregnant individuals
No

Accepts lactating individuals
No

Accepts healthy individuals
Yes

Comments about the studied populations

Healthy children aged 5 months to 10 years (Part 1) or 5-59 months (Part 2). Weight ≥5 kg and weight ≤30 kg (Part 1) or weight ≥5 kg and ≤22.5 kg (Part 2). Study participants are excluded if they have received any doses of any malaria vaccine.

Health status

Study type

Interventional (clinical trial)

Enrollment

420

Allocation

Randomized

Intervention model

Parallel 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

2024/158/CE/USTTB

Identifier

NCT06461026

Link

https://clinicaltrials.gov/study/NCT06461026

Phase

Phase I

Status

Recruiting

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

More details

The purpose of this study is to assess the safety, tolerability, and pharmacokinetics of L9LS in infants in Mali and to evaluate the impact of L9LS on subsequent R21/Matrix-MTM vaccine immunogenicity.

Purpose

L9LS MAb in Malian Infants

Interventions

Not provided

Countries

Not provided

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2024-08-19

Anticipated Date of Last Follow-up
2024-08-26

Estimated Primary Completion Date
2025-08-01

Estimated Completion Date
2025-08-01

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Children

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
Yes

Comments about the studied populations

Inclusion Criteria: 1. Age ≥1 to ≤12 months at enrollment. 2. Born at ≥37 weeks gestation. 3. Parent and/or guardian able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process. 4. In good general health and without clinically significant medical history. 5. Parent and/or guardian able to provide informed consent. 6. Willing to have blood samples and data stored for future research. 7. Resides in or near Kalifabougou, Faladje, or Torodo, Mali, and available for the duration of the study. Exclusion Criteria: 1. Body weight \<3.5 kg. 2. Behavioral, cognitive, or psychiatric disease in the parent and/or guardian that in the opinion of the investigator affects the ability of the parent and/or guardian to understand and comply with the study

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

180

Allocation

Randomized

Intervention model

Sequential assignment

Intervention model description

Not provided

Masking

Quadruple-blind masking

Masking description

Not provided

Frequency of administration

Not provided

Studied LA-formulation(s)

Not provided

Studied route(s) of administration

Not provided

Use case

Not provided

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

Wang LT, Pereira LS, Flores-Garcia Y, O'Connor J, Flynn BJ, Schön A, Hurlburt NK, Dillon M, Yang ASP, Fabra-García A, Idris AH, Mayer BT, Gerber MW, Gottardo R, Mason RD, Cavett N, Ballard RB, Kisalu NK, Molina-Cruz A, Nelson J, Vistein R, Barillas-Mury C, Amino R, Baker D, King NP, Sauerwein RW, Pancera M, Cockburn IA, Zavala F, Francica JR, Seder RA. A Potent Anti-Malarial Human Monoclonal Antibody Targets Circumsporozoite Protein Minor Repeats and Neutralizes Sporozoites in the Liver. Immunity. 2020 Oct 13;53(4):733-744.e8. doi: 10.1016/j.immuni.2020.08.014. Epub 2020 Sep 17. PMID: 32946741; PMCID: PMC7572793.

Discovering potent human monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on sporozoites (SPZ) and elucidating their mechanisms of neutralization will facilitate translation for passive prophylaxis and aid next-generation vaccine development. Here, we isolated a neutralizing human mAb, L9 that preferentially bound NVDP minor repeats of PfCSP with high affinity while cross-reacting with NANP major repeats. L9 was more potent than six published neutralizing human PfCSP mAbs at mediating protection against mosquito bite challenge in mice. Isothermal titration calorimetry and multiphoton microscopy showed that L9 and the other most protective mAbs bound PfCSP with two binding events and mediated protection by killing SPZ in the liver and by preventing their egress from sinusoids and traversal of hepatocytes. This study defines the subdominant PfCSP minor repeats as neutralizing epitopes, identifies an in vitro biophysical correlate of SPZ neutralization, and demonstrates that the liver is an important site for antibodies to prevent malaria.

Wu, R.L. et al. (2022) ‘Low-dose subcutaneous or intravenous monoclonal antibody to prevent malaria’, New England Journal of Medicine, 387(5), pp. 397–407. doi:10.1056/nejmoa2203067. 

BACKGROUND

New approaches for the prevention and elimination of malaria, a leading cause of illness and death among infants and young children globally, are needed.

METHODS

We conducted a phase 1 clinical trial to assess the safety and pharmacokinetics of L9LS, a next-generation antimalarial monoclonal antibody, and its protective efficacy against controlled human malaria infection in healthy adults who had never had malaria or received a vaccine for malaria. The participants received L9LS either intravenously or subcutaneously at a dose of 1 mg, 5 mg, or 20 mg per kilogram of body weight. Within 2 to 6 weeks after the administration of L9LS, both the participants who received L9LS and the control participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying Plasmodium falciparum (3D7 strain).

RESULTS

No safety concerns were identified. L9LS had an estimated half-life of 56 days, and it had dose linearity, with the highest mean (±SD) maximum serum concentration (Cmax) of 914.2±146.5 μg per milliliter observed in participants who had received 20 mg per kilogram intravenously and the lowest mean Cmax of 41.5±4.7 μg per milliliter observed in those who had received 1 mg per kilogram intravenously; the mean Cmax was 164.8±31.1 in the participants who had received 5 mg per kilogram intravenously and 68.9±22.3 in those who had received 5 mg per kilogram subcutaneously. A total of 17 L9LS recipients and 6 control participants underwent controlled human malaria infection. Of the 17 participants who received a single dose of L9LS, 15 (88%) were protected after controlled human malaria infection. Parasitemia did not develop in any of the participants who received 5 or 20 mg per kilogram of intravenous L9LS. Parasitemia developed in 1 of 5 participants who received 1 mg per kilogram intravenously, 1 of 5 participants who received 5 mg per kilogram subcutaneously, and all 6 control participants through 21 days after the controlled human malaria infection. Protection conferred by L9LS was seen at serum concentrations as low as 9.2 μg per milliliter.

CONCLUSIONS

In this small trial, L9LS administered intravenously or subcutaneously protected recipients against malaria after controlled infection, without evident safety concerns. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 614 ClinicalTrials.gov number, NCT05019729)

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