Therapeutics

IBC-Ab002

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Overview

Name: IBC-Ab002
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: ImmunoBrain Checkpoint

Background

This humanized IgG1 antibody inhibits an immune checkpoint protein called programmed death ligand, aka PD-L1, stimulating the immune system. Checkpoint inhibitors, including other antibodies, are approved to treat cancer, where they release tumor-induced immunosuppression and allow immune attack on malignant cells. 

The rationale for using PD-L1/PD-1 inhibitors to treat Alzheimer’s disease stems from research stimulating the peripheral immune system to recruit regulatory T cells and monocytes to the brain to improve amyloid clearance and quell inflammation (Baruch et al., 2015). Subsequent work showed that an antibody similar to the FDA-approved, anti-PD1 immunotherapy Keytruda increased infiltration of phagocytic monocytes in the 5xFAD mouse model, leading to reduced plaque load and better performance in the water maze (Baruch et al., 2016). The antibody reportedly had similar effects in the DM-HTau mouse model of tauopathy, though these findings were not corroborated (see news and commentary on Rosenweig et al., 2019; Latta-Mahieu et al., 2017; Obst et al., 2018).

In 2017, the Danish company Lundbeck announced it had acquired the rights to ImmunoBrain Checkpoint's program (press release).

According to company disclosures, IBC-Ab002 differs from other PD-L1/PD-1 antibodies in that it has a modified Fc effector region and is more rapidly cleared from the blood. Both modifications are designed to enhance safety, as checkpoint inhibitors can cause autoimmune side effects. At the 2020 AAIC, the company reported less induction of autoimmune diabetes in susceptible mice than the unmodified antibody. In preclinical efficacy studies, a single antibody dose improved cognitive performance one month later in 5xFAD, DM-HTau (K257T/P301S), and PS19 (p301S Tau) mice. Repeatedly dosed DM-HTau mice maintained improvements in T maze behavior for at least five months (see AAIC poster).

Findings

In October 2022, IBC began a Phase 1, first-in-human study to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of intravenous IBC-Ab002. The single and multiple ascending dose study plans to enroll 40 people with Alzheimer's disease into five dose groups, with placebo controls. Funded by the U.S. National Institute On Aging and the Alzheimer’s Association, the trial is running at six sites in Israel and the United Kingdom, with completion set for late 2024.

For details on IBC-Ab002 trials, see clinicaltrials.gov.

Last Updated: 03 Nov 2022

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References

News Citations

  1. Cancer Treatment Takes Aim at Tauopathy

Research Models Citations

  1. 5xFAD (C57BL6)
  2. Tau P301S (Line PS19)

Paper Citations

  1. Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A, Tsitsou-Kampeli A, Sarel A, Cahalon L, Schwartz M. Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology. Nat Commun. 2015 Aug 18;6:7967. PubMed.
  2. Baruch K, Deczkowska A, Rosenzweig N, Tsitsou-Kampeli A, Sharif AM, Matcovitch-Natan O, Kertser A, David E, Amit I, Schwartz M. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat Med. 2016 Feb;22(2):135-7. Epub 2016 Jan 18 PubMed.
  3. Rosenzweig N, Dvir-Szternfeld R, Tsitsou-Kampeli A, Keren-Shaul H, Ben-Yehuda H, Weill-Raynal P, Cahalon L, Kertser A, Baruch K, Amit I, Weiner A, Schwartz M. PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat Commun. 2019 Jan 28;10(1):465. PubMed.
  4. Latta-Mahieu M, Elmer B, Bretteville A, Wang Y, Lopez-Grancha M, Goniot P, Moindrot N, Ferrari P, Blanc V, Schussler N, Brault E, Roudières V, Blanchard V, Yang ZY, Barneoud P, Bertrand P, Roucourt B, Carmans S, Bottelbergs A, Mertens L, Wintmolders C, Larsen P, Hersley C, McGathey T, Racke MM, Liu L, Lu J, O'Neill MJ, Riddell DR, Ebneth A, Nabel GJ, Pradier L. Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-β burden in several amyloid transgenic mouse models. Glia. 2018 Mar;66(3):492-504. Epub 2017 Nov 14 PubMed.
  5. Obst J, Mancuso R, Simon E, Gomez-Nicola D. PD-1 deficiency is not sufficient to induce myeloid mobilization to the brain or alter the inflammatory profile during chronic neurodegeneration. Brain Behav Immun. 2018 Oct;73:708-716. Epub 2018 Aug 4 PubMed.

External Citations

  1. clinicaltrials.gov
  2. press release
  3. AAIC poster

Further Reading

No Available Further Reading