A D V E R T I S E R R E TA I N S S O L E R E S P O N S I B I L I T Y F O R C O N T E N T

A D V E R T I S E M E N T F E A T U R E

TAE Life Scienceswww.taelifesciences.com

Developing targeted drugs for boron neutroncapture therapy to treat refractory cancersTAE Life Sciences is developing a next-generation boron neutron capture therapy for cancer. After recently introducingAlphabeam, a compact and affordable accelerator-based neutron system suitable for hospital settings, the companyis now focusing on the development of novel boron drugs with improved tumor selectivity and increased 10B loads.

TAE Life Sciences (TLS), founded in 2017, is a pri-vately-held biotechnology company committed todeveloping next-generation boron neutron capturetherapies (BNCTs) to treat patients with invasive,recurrent and difficult to treat cancers.

BNCT is best described as a hybrid radiationmodality: following infusion of a patient with aninert, non-radioactive, 10B isotope–containingcompound that preferentially targets cancer cells,the tumor is irradiated with a low-energy neutronbeam that triggers fission of the 10B isotope. Thefission reaction releases a high-energy α–particlethat causes intracellular double strand DNA breaksleading to apoptosis. By ‘homing’ the lethal effect ofradiation to only those cells that have internalizedthe 10B isotope–containing compound, BNCT mini-mizes damage to surrounding healthy, non-tumortissues. To date, approximately 2,000 patientsworldwide have undergone BNCT and shown favor-able clinical outcomes in glioblastomas, head andneck, and other challenging cancers (Fig. 1).

Broader implementation of BNCT, however, hasbeen hampered by (1) limited access to neutronsources—until recently only available at non-hos-pital settings such as at nuclear research reactors—and (2) the limited effectiveness of current 10B iso-tope–containing compounds—the most advancedboron drug available is boronophenylalanine (BPA),a ‘passive’ drug that relies exclusively on the higheramino acid uptake rates of rapidly dividing tumorcells compared with non-tumor cells.

The introduction over the past decade of compactand affordable accelerator-based neutron sourceswell suited for a hospital setting has now removedthe physical barrier to a wider adoption of BNCT andtriggered a renewed interest in the development ofnovel 10B-containing compounds of improved targetselectivity and increased boron load.

TLS has established a comprehensive approachto the development of solutions that will enablethe implementation of next-generation BNCT asa first-line treatment for cancer patients. On theneutron source front, the company’s AlphabeamNeutron System (ANS), a positive ion-based elec-trostatic accelerator device, will provide the mostcompact, reliable and economical solution for theclinical implementation of BNCT. On the boron drugfront, TLS is advancing a pipeline of novel borondrugs for the US and European markets that include,boronated amino acid and small peptide alterna-tives to BPA, antibody boron conjugates (ABCs),and boron enriched nanoparticles.

The company is collaborating with leading can-cer research centers globally to deploy the ANSand establish clinical BNCT facilities, at the sametime securing partnerships with key academic andclinical institutions around the world to drive theresearch of novel boron drugs for improved tumorselectivity and delivery of exponentially higher 10Bloads to the target cells than current drugs. In-houseintegration of both efforts allows for the engineeringof optimal and complete BNCT systems.

“At TLS we have assembled a world-class, cross-functional team of clinicians, radiation oncologists,physicists, and other researchers to bring BNCTto cancer patients with the most aggressive andrecurrent cancers,” said Bruce Bauer, CEO of TLS.“With in-hospital access to a neutron source nowbecoming a reality, TLS is making a significantinvestment in developing a portfolio of new boro-nated compounds to help expand the applicationof BNCT to new cancer types and to provide evenbetter outcomes for indications historically treatedwith BPA.”

Next generation boron drugsIn March 2020, the Japanese Pharmaceuticals andMedical Devices Agency approved the first everBNCT system, consisting of a medical-grade accel-erator, a dose calculation program and a treatmentplanning platform. This was shortly followed by theapproval of BPA for the treatment of advanced andrecurrent head and neck cancer, and a June rulingby the Japanese National Health Insurance allowingreimbursements for BNCT.

Against this backdrop, TLS is now expediting thecommercialization of the intravenous formulation ofBPA, for approval in the US and in Europe. In parallel,TLS is also readying its ANS for regulatory submis-sion both in the US and in Europe, with a targetdate for first installations of 2022. The initial targetindications for TLS’ BNCT system will be advancedand recurrent head and neck cancer, gliomas, andmelanomas—all cancers treated historically withBPA. The goal is to start clinical trials in the US andin Europe in the next 2 to 3 years.

Although clearly effective and an excellent first-generation boron drug for BNCT, BPA has limitationsin achieving the levels of tumor cell targeting and10B delivery necessary for therapeutic applicationacross a broad range of cancer types. To achievethe full potential of BNCT, improved boron-carryingdrugs need to be developed. TLS is already workingtoward this goal by designing more effective nextgeneration boron drugs that address the fundamen-tal limitations of BPA.

First, and in order to maximize the effectivenessof BNCT, the 10B load per cell must be improved.Current estimates are that a boronated drug shoulddeliver at least 20�μg of 10B per gram of tumor. WithBPA carrying only one boron atom per molecule,there is room to improve the cellular load byaugmenting the number of atoms per boron drugmolecule internalized.

Second, the specificity of the boronated com-pounds for tumor cells has to be maximized. Theminimal tumor to healthy cell boron ratio for asuccessful BNCT is 3:1. With BPA uptake being

IV administeredtargeted boron drug

1 Tumor irradiatedwith safe neutrons

2 Boron captures neutrons and emits alphaand Li particles destroying cancer cell

3

Normal cellNeutrons

Boron (10B)

7Li particle

α particle

Cancer cell

Thermal neutron

Nucleus

Fig. 1 | TAE Life Sciences’ next-generation BNCT for cancer. Following infusion with an inert, non-radioactive, 10B isotope–containing compound that preferentially targets cancer cells, the patient isirradiated with a low-energy neutron beam that triggers fission of the 10B isotope in tumor cells. Thefission reaction releases a high energy α–particle that causes apoptosis in only those cells that haveinternalized the 10B isotope–containing compound.

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A D V E R T I S E R R E TA I N S S O L E R E S P O N S I B I L I T Y F O R C O N T E N T

A D V E R T I S E M E N T F E A T U R E

determined solely by the enhanced metabolic needsof cancer cells, the typical ratios achieved with ithover around that lower range, leaving room forimprovement by increasing the selectivity of theboron drugs for cancer cells.

While the short path length of the high energyα–particles generated following the fission reactionguarantees their destructive effect is kept within thecellular confines—making BNCT a safe therapeuticoption—efficacy of the method relies on the abilityto deliver the boronated compounds to all or asmany tumor cells as possible. While BPA performswell in terms of diffusion into tumors, a variety ofmedicinal chemistry tools will help improve intra-tumoral diffusion and optimize dosing of novelboron drugs.

TLS is addressing all of these issues with a pipelineof diverse drug development approaches supportedby a number of different patented molecular designsand scalable synthetic routes. Initial results arealready showing superior 10B delivery comparedto existing 10B carriers.

Small moleculesSmall molecules are a way to treat many diseasesincluding cancer. In particular, small moleculesare well suited for the treatment of brain tumorsbecause the size of the compounds enables themto cross the blood–brain barrier and engage tar-gets in the brain. TLS is developing novel boronatedamino acids and other small molecules of increased

solubility, improved cell uptake and retention andeasier formulation than BPA. The company’s leadcompound is TDP-747, an amino acid analoguethat is taken up by the large neutral amino acidtransporter (LAT-1), which is upregulated in manycancers. In vivo, TDP-747 shows a tumor to healthycell boron ratio of 13:1, a vast improvement over the3:1 ratio usually seen with BPA.

Antibody boron conjugatesTo address the issue of specificity, TLS is leveragingsome antibody–drug conjugate (ADC) technologyto develop antibody boron conjugates (ABCs) forimproved differential penetration of boron drugsinto tumor cells. ABCs consist of an antibody moi-ety and a boron-containing payload. Unlike smallmolecules such as amino acids, ABCs are designedto specifically target tumor cells and they have alonger serum half-life. To facilitate ABC develop-ment, TLS is developing boron enriched linkers(BELs) capable of carrying large 10B loads. Theselinkers can be modified for size, charge, stability, andbranching (Fig. 2). In proof-of-concept studies, TLShas succeeded to generate loads of up to 400 boronatoms per antibody using lysine conjugation andBELs. Such high-load ABCs should help improve theefficacy of BNCTs, as well as expand the spectrumof cancer indications treatable with BNCT.

NanoparticlesIn collaboration with Kyoto University, TLS is alsodeveloping a novel class of nanoparticle carri-ers called BPMOs (biodegradable mesoporousorganosilica nanoparticles) that can carry large10B loads and deliver them with high selectivity tocancer cells. Nanoparticles of the size being madeunder this collaboration have been shown to hometo tumor cells as a result of what is known as anEPR effect, enhanced penetration and retention.Chick embryo studies with BPA-loaded BPMOshave already shown high efficacies and specifici-ties, pointing to the potential of these nanopar-ticles for BNCT. In vivo studies in animal modelsare now planned.

“The approval of the first complete BNCT platformlast year in Japan signaled the start of a new era forradiation-based treatment of cancer,” said Bauer.“At TLS we are committed to expanding the appli-cation of BNCT to a broader list of cancer types,and to improve outcomes for indications histori-cally treated with BPA, through the developmentof a portfolio of novel targeted boron drugs thatwill help increase the safety and efficacy of BNCTexponentially.”

Partnering BNCTTLS has a mission to develop BNCTs to help improvethe lives of patients with invasive, recurrent anddifficult to treat cancers. Because BNCT representsthe sum of multiple technologies, TLS has adopteda collaborative strategy to allow it to incorporatethe most advanced solutions for each technologyinvolved in BNCT—from the neutron source to thetumor cell targeting moiety.

TLS has several agreements in place to install itsANS in different locations around the world and isestablishing a network of collaborations to developother components of the BNCT system.

“The ongoing BNCT renaissance has been fueledmostly by the technological advances on the neu-tron source front,” said Bauer. “New windows ofopportunity have now opened for the developmentof novel boron drugs to capitalize on the potentialof BNCT, and we believe this will be best achievedthrough collaborative approaches that keep patientsand their wellbeing as a main focus.”The TLS’ Alphabeam Neutron System and boron drugs are indevelopment and are not available commercially.

Anna Theriault, Global VP,Marketing & StrategyTAE Life SciencesFoothill Ranch, CA, USATel: +1-949-830-2117Email: contact@taelifesciences.com

CON

TACT

Cell is irradiatedwith neutrons

3Boron (10B)

Neutrons

• Improved targeting• Higher boron uptake in tumor• Longer boron retention• Improved radiotherapy e�ciency

Tumor-specific target

Thousands of tumor-specific targets arefound on the surface of a tumor cell

ABCs with BELscarrying boron-10payload binds toreceptors oncell surface

1

Internalization and endosomal/lysomal degradationof ABC–receptor complex releasing boron

2

Boron absorbs neutrons and disintegratesemitting lethal radiation that causesDNA double-strand breaks and otherorganelle damage

4

Fig. 2 | Antibody boron conjugate with BELs. Traditionally, boron neutron capture therapies (BNCT) have relied on the incorporation of boronophenylalanine intumor cells due to their higher amino acid uptake rates compared with non-tumor cells. TLS’ novel approach relies on the use of antibodies loaded with boron-enriched linkers (BELs) with the goal to improve targeting and increase both specificity for tumor cells and boron-loading of the cells for BNCT. ABC, antibodyboron conjugate.

“The approval of the firstcomplete BNCT platform

last year in Japan signaledthe start of a new era forradiation-based treatmentof cancer

Bruce Bauer, CEO,TAE Life Sciences

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