Alpha Program

CLR 121225 (CLR 225): Alpha Emitter (²²⁵Ac)

An investigational targeted radioconjugate designed to deliver potent alpha-emitting radiation for the treatment of solid tumors.

Program Overview

CLR 225 is an investigational phospholipid ether (PLE) radioconjugate designed to deliver actinium-225 (²²⁵Ac), a potent alpha-emitting isotope, directly into cancer cells.

This approach leverages Cellectar’s proprietary PLE platform to selectively target tumor cell membranes, enabling localized delivery of cytotoxic radiation while sparing normal tissue.

Key Points

Targets cancer cells through PLE-mediated uptake
Delivers high-linear-energy-transfer (LET) alpha emissions for potent localized cell killing
Designed to minimize collateral tissue damage due to short-range emission (< 100 μm)
Structurally consistent with iopofosine I-131, supporting development efficiency

Mechanism of Action

How Alpha Emitters Work

Alpha emitters release high-energy helium nuclei that create dense ionization tracks within a few cell diameters, producing double-strand DNA breaks and rapid, irreversible cell death.

CLR 225 uses Cellectar’s PLE targeting to internalize these alpha emissions directly within tumor cells, concentrating the therapeutic effect precisely at the disease site.

Scientific Highlights

Double-strand DNA damage via high-LET alpha particles
Intracellular delivery limits radiation exposure to healthy cells
Designed for deep tumor penetration with controlled toxicity profile

Preclinical Efficacy

Tumor Volume Reduction and Survival Benefit in Pancreatic Cancer

In preclinical pancreatic cancer models, CLR 225 produced a clear, dose-dependent reduction in tumor volume and extended survival across all tested groups.

The compound was well tolerated at every evaluated dose, demonstrating both potent antitumor activity and a favorable safety profile.

Key Findings

Tested in three xenograft models (MIA PaCa-2, PANC-1, BxPC-3)
Dose-response pattern consistent across all models (Cold, 100 nCi, 250 nCi, 500 nCi)
Tumor volume reduction and improved survival observed at every dose
No dose-limiting toxicities detected

Tumor Reduction

Survival Benefit

Tolerated Doses

Biodistribution

High and Prolonged Tumor Uptake with Low Normal Tissue Uptake

CLR 225 demonstrated selective tumor accumulation and retention in preclinical pancreatic models, with minimal uptake in non-target organs.

Highlights

Sustained tumor uptake > 144 hours
Minimal uptake in critical normal tissues (liver, kidney, heart)
Favorable tumor-to-blood ratio supporting targeted delivery

High and prolonged tumor uptake; low normal tissue uptake

Clinical Evaluation

Phase 1 Imaging and Therapy Study in Pancreatic Cancer

CLR 225 will be evaluated in a Phase 1 clinical study to assess safety, biodistribution, and dose-limiting toxicities using an accelerated titration design.

Study Overview

Imaging and therapy study
Accelerated intrapatient dose escalation for early determination of tolerability
Dose-limiting toxicities assessed post-Cycle 1 Day 57
Standard 3+3 escalation following initial titration

Excellent labeling efficiency with ²²⁵Ac

Simplified reaction process

Preferred formulation for toxicity studies (no polysorbate needed)

Phase 1 study design

Imaging and therapy study

Dose escalation utilizing an accelerated titration design (allows intrapatient dose escalation for more rapid dose escalation); dose limiting toxicities to be assessed post-cycle 1 day 57

Dose escalations = 40% increases until first moderate toxicity; then standard 3+3 escalation

Single Ascending Doses and Multiple Ascending Doses

Development Pathway

Extending the PDC Platform with Alpha Emitters

CLR 225 represents Cellectar’s continued expansion into high-LET alpha therapeutics, complementing beta- and Auger-based programs in development.

Compliance Statement

CLR 225 is an investigational agent and has not been approved by the U.S. Food and Drug Administration or any other regulatory authority.

Safety and efficacy have not been established.