Alector Showcases ABC Brain-Delivery Platform, AL137 and AL050 Updates at TD Cowen Conference

Key Points

• ABC epitope on the transferrin receptor is Alector’s key differentiator—binding the side epitope drives substantially higher brain uptake in nonhuman primates while reducing Fc-mediated safety liabilities like sustained reticulocyte depletion versus more exposed TfR epitopes.
• AL137, an ABC-enabled anti-amyloid antibody, produced >12-fold higher CSF levels and ~30-fold higher parenchymal brain levels versus a non-ABC antibody in NHPs, was well tolerated, and is being pushed toward an IND by year-end/early next year with first-in-human SAD/MAD studies (including a subcutaneous arm) planned to read out amyloid PET effects.
• ABC-enabled AL050 and siRNA programs demonstrate platform versatility: AL050 is an engineered GCase (~50x activity, much greater stability) that increased brain enzymatic activity and uptake in NHPs with good tolerability, and ABC-delivered siRNA showed up to ~70% tau mRNA knockdown and sustained CSF tau reductions after peripheral dosing in primate studies.

Alector NASDAQ: ALEC used a presentation at the 46th Annual TD Cowen Healthcare Conference to highlight progress on its Alector Brain Carrier (ABC) platform, which is designed to deliver multiple therapeutic “cargos” across the blood-brain barrier using the transferrin receptor (TfR). Eric Brown, head of antibody discovery and protein engineering, said he would focus on ABC-enabled programs and not discuss AL101, which is undergoing an interim futility analysis in the first half of this year.

ABC platform focus and TfR epitope selection

Brown said Alector began work on its blood-brain barrier platform roughly seven years ago by evaluating several receptors, including transferrin receptor (TfR), CD98, and IGF1R, and ultimately narrowed its efforts to TfR as the most “ready for platform applications.” He said the company has applied ABC technology to 13 cargos—antibodies, enzymes, and siRNAs—testing many in vivo and in non-human primates (NHPs).

A key differentiator, according to Brown, is Alector’s choice of TfR binding epitope. He contrasted a commonly used “tip of the apical domain” epitope—where other programs bind and where antibody Fc regions may be more exposed to immune effector interactions—with Alector’s proprietary “ABC epitope” located on the side of TfR. Brown said binding at the ABC epitope does not interfere with transferrin binding and can drive strong brain uptake while reducing safety liabilities associated with Fc-mediated effects.

He described in vitro and in vivo data intended to show reduced antibody-dependent cellular cytotoxicity (ADCC) signaling and reduced reticulocyte depletion for antibodies binding the ABC epitope compared with an exposed epitope, including NHP toxicology dosing studies where the ABC epitope approach showed transient reticulocyte decreases with recovery between doses and no sustained declines in red blood cells or hemoglobin.

Brown also emphasized that translating performance from mice to NHPs has been a major learning, saying antibodies that drive similar brain uptake in mice can show substantial differences in NHPs, with Alector selecting candidates showing the highest fold increases in primate brain uptake.

ABC-enabled anti-amyloid antibody: AL137

Brown presented data on AL137, an anti-amyloid beta (Aβ) antibody enabled by ABC technology. He said the company is pairing an anti-Aβ approach targeting pyroglutamate Aβ with a fully active wild-type IgG1 Fc, arguing that effective clinical Aβ-clearing antibodies have generally relied on an active IgG1 format. Instead of tuning down Fc activity for safety, Brown said Alector aims to maintain potency and manage safety through its ABC epitope selection.

He said AL137 has been designed for manufacturability and high concentration (up to 150 mg/mL) with subcutaneous administration as a long-term goal. Alector plans to include both IV and subcutaneous dosing in its first-in-human study.

In NHP studies, Brown said AL137 drove more than a 12-fold increase in cerebrospinal fluid (CSF) levels at 24 hours versus a non-ABC “naked” antibody. In vessel-depleted brain tissue fractions intended to reflect parenchymal uptake, he cited approximately 30- to 32-fold higher levels versus the naked antibody. He also described an “absolute brain uptake” benchmark in frontal cortex after a 3 mg/kg dose and said the company compared that result to published NHP data from other programs, asserting higher brain accumulation at a lower dose.

On safety, Brown said AL137 was well tolerated in NHPs at both a 3 mg/kg therapeutic dose and a 30 mg/kg toxicology dose. He noted transient reticulocyte reductions with full recovery by the next weekly dosing interval at the therapeutic dose, and said there were no declines in red blood cells or hemoglobin and no test-article related adverse findings in the study. Brown said the company is moving AL137 toward an IND filing by the end of this year, “maybe slipping into early next year,” with first-in-human dosing planned relatively soon after.

ABC-enabled GCase enzyme: AL050

Brown also discussed AL050, an ABC-enabled glucocerebrosidase (GCase) enzyme program aimed at GBA-associated Parkinson’s disease (PD) and Lewy body dementia. He described two hurdles: delivering an enzyme across the blood-brain barrier and producing GCase, which he characterized as difficult to manufacture. Brown said Alector engineered a version of GCase that is approximately 50 times more active than wild-type and improved stability in serum-like conditions from less than six hours to more than a week, then paired it with a TfR ABC format intended to drive brain and neuronal uptake.

In mouse studies with a surrogate molecule, Brown said Alector observed increased GCase activity and reductions in toxic substrates (including glucosylsphingosine) in a GBA knockout model, with substrate reduction lasting beyond four weeks after a single dose. In NHPs, he cited improved plasma activity half-life versus wild-type enzyme replacement approaches and increased brain uptake (reported as 5- to 18-fold versus a non-TfR-binding control format). He also said the program drove increases in enzymatic activity across brain regions, describing a 63% to 132% increase in healthy monkeys.

Brown said AL050 was well tolerated in NHPs, with no AL050-related clinical signs, no hematology impact, and no transient reticulocyte reductions, attributing this to using the ABC epitope and a silenced Fc.

siRNA delivery enabled by ABC and tau program data

Brown said Alector has also extended ABC to siRNA delivery, aiming to avoid intrathecal administration by enabling peripheral dosing such as IV and subcutaneous. He said the company partnered with Axolabs to develop potent and specific siRNAs and described a murine proof-of-concept SOD1 study in which IV-dosed, ABC-enabled siRNA showed stronger knockdown across brain regions than an intracerebroventricular (ICV) comparator in the study design he referenced.

For its tau program, Brown described NHP repeat-dose data (three doses at 3 mg/kg siRNA equivalent) showing brain-region siRNA accumulation and up to 70% tau mRNA knockdown across regions. He also described protein-level changes including reductions in phospho-tau 217 at day 28 and reductions in CSF tau out to day 49 and day 70, reaching up to about a 50% decrease in CSF tau. Brown said a 30 mg/kg siRNA-equivalent toxicology dose was also tested with no adverse events, no hematology effects, and no increases in liver enzymes or inflammatory proteins.

Clinical path for AL137 and update on AL101 interim futility analysis

In Q&A, Alector executives reiterated that subcutaneous administration is a goal across programs, with Brown saying the Aβ program has “a very clear path” to subcutaneous dosing based on modeling suggesting sufficient coverage below the 3 mg/kg dose shown. He said subcutaneous dosing for AL050 and siRNA programs remains a goal but depends on final efficacious dose and formulation feasibility.

Giacomo (identified during Q&A as part of management) outlined a proposed clinical plan for AL137, citing an IND timeline of Q4 this year or Q1 2027 depending on clinical supply availability. He said the company plans to begin with a single ascending dose study in healthy volunteers, including a subcutaneous arm, and then move quickly to a multiple ascending dose study in patients with early Alzheimer’s disease (mild cognitive impairment and mild AD). He said an important readout will be amyloid clearance measured by amyloid PET and suggested an effect could be detectable with 10 to 15 patients. He described a Phase 1 goal of demonstrating decreased brain amyloid with subcutaneous delivery “without significant ARIA above the background level” and without clinically significant anemia.

Management also addressed the ongoing AL101 interim futility analysis, stating it will be conducted by an independent data monitoring committee in the first half of this year using pre-specified futility criteria based on clinical efficacy measures and biomarkers. They said the outcome will be binary—stop for futility or continue as planned—and that the sponsor will not have visibility into effect magnitude or detailed drivers of the decision unless the study is stopped and the data are reviewed. If continued, they said the study is planned to run through last patient out at the end of 2026.

About Alector NASDAQ: ALEC

Alector is a clinical-stage biotechnology company headquartered in South San Francisco, California. Founded in 2013, the company is focused on discovering and developing immuno-neurology therapies that target the innate immune system to treat a range of neurodegenerative disorders. Alector's approach aims to harness the body's natural defense mechanisms to clear pathological proteins and restore neuronal function in conditions such as Alzheimer's disease and frontotemporal dementia.

The company's pipeline includes multiple product candidates in both preclinical and clinical stages, with lead programs AL001 and AL002 advancing in frontotemporal dementia and Alzheimer's disease studies.

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