ANG1005

ANG1005, paclitaxel trevatide, GRN1005; platform: Angiopep-2, "Engineered Peptide Compound" conjugates

Oncology & imaging

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Summary

Class: Peptide-drug conjugate: Angiopep-2, a 19-amino-acid peptide derived from the aprotinin sequence, covalently linked to three molecules of paclitaxel
Mechanism: The Angiopep-2 peptide binds LRP1 on brain capillary endothelium and is carried across the blood-brain barrier by receptor-mediated transcytosis, taking its chemotherapy payload with it
Routes studied: Intravenous infusion, every three weeks
Half-life: Short in plasma; the conjugate is cleared over hours with paclitaxel released intracellularly †
Storage: Investigational cytotoxic product handled and prepared by hospital pharmacy under trial protocol
Regulatory status: Not approved anywhere. FDA Fast Track designation granted for breast cancer brain metastases; development status uncertain at the time of review †

Doses are as reported in studies or by the community — never recommendations.

1What it is

The blood-brain barrier is the central problem in neuro-oncology and in CNS drug development generally: tight junctions between brain capillary endothelial cells, plus active efflux pumps, keep most large or polar molecules out. Paclitaxel is a highly effective chemotherapy that barely enters the brain, which is why brain metastases are often treated with radiation rather than drugs.

Angiopep-2 is a 19-amino-acid peptide derived from the Kunitz domain of aprotinin, selected for its ability to bind LRP1 (low-density lipoprotein receptor-related protein 1), a receptor expressed densely on brain capillary endothelium and on many tumour cells. LRP1 shuttles its ligands across the endothelial cell by transcytosis. Conjugate a drug to Angiopep-2 and, in principle, it rides across. ANG1005 is that idea in its most developed form: three paclitaxel molecules attached to one Angiopep-2 peptide.

This profile covers both the specific compound and the platform, because the platform idea — a short peptide as a shuttle for molecules that cannot cross the barrier on their own — matters more than any one conjugate. It is investigational throughout; nothing from this platform is approved.

2How it's thought to work

LRP1 binding. Angiopep-2 binds LRP1 on the luminal surface of brain capillary endothelial cells. LRP1 is a scavenger receptor with many natural ligands and high expression at the barrier.

Receptor-mediated transcytosis. The peptide-receptor complex is internalised into a vesicle, carried across the endothelial cell, and released on the brain side. This is an active transport route, distinct from passive diffusion or from disrupting the barrier.

Payload release. Once in brain tissue and taken up by tumour cells — which also often express LRP1 — esterase cleavage releases paclitaxel, which stabilises microtubules and kills dividing cells.

Efflux avoidance. Because the conjugate crosses inside a vesicle rather than through the membrane, it is reported to be less subject to P-glycoprotein efflux than free paclitaxel.

Platform generality. The same peptide has been conjugated to other payloads, including other cytotoxics, antibody fragments, enzymes for lysosomal storage disease and nucleic acids, in preclinical work. Related shuttle approaches use transferrin receptor or insulin receptor binders rather than LRP1.

A peptide that uses LRP1, a transporter the brain already runs, to carry three molecules of paclitaxel across the blood-brain barrier. The peptide is the key; the drug is the cargo, and it could not cross on its own.Schematic — not to scale

3What the research shows

Breast cancer brain metastases, Phase 2

A Phase 2 trial of ANG1005 in patients with HER2-negative breast cancer and recurrent brain metastases, including a leptomeningeal carcinomatosis cohort, reported intracranial disease control and an intracranial objective response rate in the region of 15–20%, with clinical benefit in a subset and median overall survival figures the sponsor presented as favourable against historical comparison (Kumthekar 2020, Clin Cancer Res). Single-arm, with historical rather than randomised comparison — this is the ceiling of the current evidence. [1]

Phase 1 and early Phase 2 in brain tumours

Phase 1 trials in recurrent high-grade glioma and in solid tumours with brain metastases established dosing at 550–650 mg/m² every three weeks and reported radiographic responses in a minority, with toxicity consistent with paclitaxel (Drappatz 2013, Clin Cancer Res; Kurzrock 2012, Mol Cancer Ther). [2][3]

Direct evidence of brain penetration

Surgical studies measuring drug in resected brain tumour tissue after infusion reported detectable paclitaxel in tumour at concentrations above what free paclitaxel achieves. This is the most important supporting evidence for the platform, because it addresses the mechanism directly rather than inferring it from response rates.

Not gradednot reported

Phase 3

A randomised Phase 3 trial in leptomeningeal disease from breast cancer (ANGLeD) was initiated. No positive Phase 3 result has been published and the programme's current status is unclear †. Readers should not assume the drug is in active late-stage development.

Graded C/D

The platform beyond ANG1005

Angiopep-conjugated payloads have shown brain delivery in rodent models across several molecule classes. Almost all of this is preclinical. The broader field of receptor-mediated brain shuttles has produced one notable clinical success in a different modality (a transferrin-receptor-binding fusion enzyme for a lysosomal storage disease approved in Japan), which supports the general principle without validating this particular peptide. Community use: essentially none documented. An investigational intravenous cytotoxic conjugate; there is no self-directed use and no plausible route to one.

4Reported side effects and interactions

Literature-reported

Literature. Toxicity in trials was essentially that of paclitaxel — neutropenia (often dose-limiting), anaemia, alopecia, peripheral neuropathy, fatigue, nausea, hypersensitivity and infusion reactions. Hypersensitivity is relevant because the conjugate avoids the Cremophor vehicle used in conventional paclitaxel but the payload itself remains immunologically relevant †.

Serious. febrile neutropenia and infection; peripheral neuropathy that can be cumulative and persistent.

Community-reported

none; no community use exists.

Theoretical. LRP1 is expressed widely outside the brain, including in liver, lung and vascular tissue, so "brain-targeted" overstates the selectivity — the platform improves brain access without confining the drug to brain. A delivery system that opens a route into the CNS also raises the question of what else it might carry across, which is relevant to the platform's safety assessment generally.

Interactions. as for paclitaxel — CYP2C8 and CYP3A4 inhibitors and inducers alter exposure; additive myelosuppression and neuropathy with other cytotoxics; live vaccines contraindicated during treatment.

Markers researchers commonly monitor

From the trial protocols and from paclitaxel toxicity management:

Marker	Why it's watched
Intracranial response on contrast MRI (RANO-BM criteria)	the endpoint that defines whether the delivery concept is working clinically.
Cerebrospinal fluid cytology	in leptomeningeal disease, the direct measure of disease in the compartment the drug is designed to reach.
Neurological examination and patient-reported neurocognitive function	brain metastases cause deficits; improvement or stabilisation is the clinically meaningful outcome.
Full blood count with differential	neutropenia is dose-limiting; checked before each cycle.
Peripheral neuropathy grading	cumulative paclitaxel toxicity, assessed every cycle.
Liver enzymes and bilirubin	paclitaxel is hepatically metabolised.
Extracranial disease response	because systemic exposure is substantial, not confined to brain.
Drug concentration in resected tumour tissue	only in dedicated surgical studies, but it is the measurement that actually tests the platform.

Free for everyone. Safety information is never behind a paywall.

5Formulation and administration context

Investigational intravenous cytotoxic conjugate, supplied and prepared by hospital pharmacy under trial protocol with full cytotoxic handling, given as an infusion every three weeks with the usual premedication and monitoring. There is no outpatient, oral or self-administered form, no guidance for anyone outside a pharmacy, and nothing in this section applies to any other setting.

6Commonly studied alongside

Radiotherapy (whole-brain or stereotactic) as the standard comparator in brain metastases; trastuzumab and other HER2-directed agents in HER2-positive disease where different approaches apply; melflufen (#248) as the other peptide-drug conjugate in this library. Conceptually adjacent: transferrin-receptor and insulin-receptor brain shuttle platforms, and peptide radiopharmaceuticals, which use peptide targeting for a different purpose.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	Not FDA-approved; investigational. Fast Track designation granted for breast cancer brain metastases; current development status unclear †
European Union	Not authorised; investigational
United Kingdom	Not licensed
Australia	Not approved
South Africa	Not registered
Sport	Not relevant; cytotoxic chemotherapy is not a doping agent and is not listed

8Open questions

Whether a randomised trial can show survival or quality-of-life benefit, which no trial has yet done.
How much of the observed activity is brain delivery versus systemic paclitaxel effect.
Whether LRP1-mediated transcytosis saturates at therapeutic doses, capping how much drug can be delivered.
Whether the Angiopep platform works better with a payload other than a taxane — a targeted agent, an antibody fragment or an enzyme.
What the current development status of ANG1005 actually is †.

9References

1Kumthekar P et al. (2020). ANG1005, a brain-penetrating peptide-drug conjugate, shows activity in patients with breast cancer with leptomeningeal carcinomatosis and recurrent brain metastases. Clin Cancer Res. PubMed · DOI
2Drappatz J et al. (2013). Phase I study of GRN1005 in recurrent malignant glioma. Clin Cancer Res. PubMed · DOI
3Kurzrock R et al. (2012). Safety, pharmacokinetics, and activity of GRN1005, a novel conjugate of angiopep-2, a peptide facilitating brain penetration, and paclitaxel, in patients with advanced solid tumors. Mol Cancer Ther. PubMed · DOI
4Demeule M et al. (2008). Identification and design of peptides as a new drug delivery system for the brain. J Pharmacol Exp Ther. PubMed · DOI
5Régina A et al. (2008). Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2. Br J Pharmacol. PubMed · DOI
6Demeule M et al. (2008). Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector Angiopep-2. J Neurochem. PubMed · DOI

† Being confirmed by our reviewers against current sources.

10Community

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Self-reported side effects Phase 2

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11Page history

31 Oct 2026Profile published — awaiting medical review

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