Targeting microglia, can Alector Alzheimer's disease antibody enter Phase 2 clinical trials, can it escape the fate of "safe and ineffective"?

Since neurodegenerative diseases were first described 100 years ago, scientists have referred to a class of diseases caused by degeneration of neurons and their myelin as neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s Disease (PD), Lewy Body Dementia (DLB), Anterior Temporal Dementia (FTD), Huntington’s Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Different Types of Spinocerebellar Ataxia (SCA), Pick’s Disease, etc.
.

With the increasing aging, Alzheimer's disease has become an important factor that threatens the quality of life and lives of elderly people.
In the United States, AD is the sixth cause of death for people over 65 years of age.

Microglia and Alzheimer’s disease Alzheimer’s disease is a molecular and genetically complex disease characterized by extensive loss of synapses and neurons (which subsequently leads to loss of brain volume), causing memory and cognitive functions The gradual decline, the inability to carry out normal daily activities later, and even death.

Cerebral pathology includes β-amyloid β (Aβ) oligomers and insoluble plaques, hyperphosphorylation of Tau in neurons, synaptic dysfunction, and neuronal cell death.

AD lesions trigger the re-expansion of reactive microglia, gathering around Aβ plaques, limiting their spread.

Disease-associated microglia (DAM), which are different from steady-state microglia, have 47H ultrapure missense mutations of TREM2, etc.
, which cause microglia lipid recognition disorders.

TREM2 of microglia (Reference 2) TREM2 is a lipid receptor expressed in microglia and macrophages of other tissues.
It is a wide range of lipids associated with β-amyloid accumulation and neuronal loss.
The sensor transmits intracellular activation signals through the adaptor DAP12 to promote the survival and proliferation of microglia, limit the accumulation of Aβ, and reduce neuronal damage.

AL002 targets microglia.
AL002 is a TREM2 agonistic antibody developed by Alector.
By promoting the activation of TREM2, it activates microglia and induces their proliferation, promotes the phagocytosis of Aβ, and delays the appearance and progression of Alzheimer's disease.

Recently, researchers from Alector and Washington University School of Medicine published the research data of AL002 in mouse model and clinical phase 1 in the famous medical journal J.
Exp.
Med.
(Reference 1).

Research data Mouse model experimental data show that AL002c (a variant of AL002) can reduce the formation of fibrous plaques.

AL002 can increase the phagocytosis of Aβ by microglia.

In the figure below, the green is CD68 (microglia activation and phagosome marker), and the red is Aβ42.

AL002 reduces the number, volume and coverage of dysplastic neurons in plaques.

The clinical phase 1 has been completed, with good safety and tolerability, and no serious side effects have been found.

NCT03635047, A Phase I Study for Safety and Tolerability of AL002.
The study of biomarkers in cerebrospinal fluid (sTREM2, sCSF-1R) initially showed its effectiveness.

STREM2 in the cerebrospinal fluid is produced by the protease hydrolysis of TREM2 on the surface of microglia.
AL002 can reduce the shedding of membrane TREM2.

sCSF-1R is only expressed by microglia, so its shedding amount increases, which indirectly indicates an increase in microglia production.

About AlectorAlector (NASDAQ:ALEC) was founded in May 2013.
It is a biopharmaceutical company located in South San Francisco.
It is mainly engaged in the development of neurodegenerative diseases and cooperates with Abbvie; its tumor immunity SIRPa antibody cooperates with Cinda.

Drugs in pre-clinical and clinical stages (from Alector's official website) are currently being recruited for phase 2 clinical trials of AL002.

NCT04592874, A Phase 2 Study to Evaluate Efficacy and Safety of AL002 in Participants With Early Alzheimer's Disease (INVOKE-2), in cooperation with AbbVie, plans to recruit 265 early Alzheimer's patients.

The editor concludes that Alzheimer's disease is an unmet clinical need, and major pharmaceutical companies have invested huge sums of money, but they have lost ground.

Alector chose to develop agonistic TREM2 antibodies to activate disease-related microglia, enhance the phagocytosis of Aβ, clear plaques, and restore neuronal function.

The clinical phase 1 has good safety and biomarkers have shown that it can activate microglia and induce their proliferation.
At present, phase 2 clinical recruitment has begun.

However, TREM2 is also involved in many functions such as nerve axon pruning.
TREM2R47H mutant microglia can bind to PtdSer on neuron axons through TREM2, swallow neuron axons and cause axon damage.
This is Alzheimer’s Another pathological mechanism of disease.

Although AL002 can activate microglia containing the TREM2 R47H mutation and increase the phagocytosis of Aβ; but there is no data showing that it can block the phagocytosis of neuronal axons by microglia.
Will it be "safe and ineffective" like other drugs in the future What? Still need to pay attention to its future phase 2 and 3 clinical trial results.

TREM2R47H mutant microglia phagocytic neuron axons (Reference 3) Reference source 1.
Shoutang Wang et al, Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model, J.
Exp.
Med.
2020 Vol.
217 No.
92.
Wang et al.
, 2015, TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer's Disease Model, Cell 160, 1061–10713.
M.
Gratuze et al.
, Impact of TREM2R47H variant on tau pathology-induced gliosis and neurodegeneration , J.
Clin.
Invest.
130, 4954-4968 (2020) The copyright statement welcomes personal forwarding and sharing.

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