Table 2.

Preclinical targeted alpha-particle therapy (TAT) studies.

Isotope	Study	Molecular Target	Targeting Moiety	Drug(s) & Route	Cancer Type & Animal Model	Key Results	Ref
225Ac	Efficacy, toxicity	PSMA, CD19	J591 & B4 mAbs	225Ac–DOTA–J591, 225Ac-B4, i.v.	Human LNCaP prostate s.c. xenografts & disseminated Daudi lymphoma in male nude mice.	Both effective without toxicity.	[35]
225Ac	Efficacy, toxicity	HER-2/neu	Trastuzumab	225Ac–DOTA–trastuzumab, i.p.	SKOV3 human ovarian cancer s.c. xenografts in female nude mice.	Effective with no toxicity.	[148]
225Ac	PK, RD, toxicity	CD33	HuM195 Ab	225Ac–DOTA–HuM195, i.v.	Cynomolgus monkey leukemia (does not express the human CD33 target).	12 d blood T1/2, dosimetry kinetics estimated, efficacy without renal toxicity.	[149]
225Ac	BD, efficacy, toxicity	Ganglioside GD2	3F8 Ab	225Ac–DOTA–3F8, i.v.	NMB-7 human neuroblastoma xenografts in nude mice (BD), meningeal carcinomatosis xenografts in nude rats (efficacy) & cynomolgus monkeys (toxicity).	Tumor specificity, increased survival, no toxicity.	[150]
225Ac, 177Lu	BD, efficacy, toxicity	Somatostatin receptors	DOTATOC peptide	225Ac and 177Lu–DOTATOC, i.v.	AR42J rat pancreatic exocrine s.c. xenografts in nude mice.	225Ac-TAT had greater efficacy relative to 177Lu-TBT with low toxicity.	[151]
225Ac, 213Bi, 90Y	BD, dosimetery, efficacy, toxicity	HER-2/neu	7.16.4 mAb	225Ac, 213Bi and 90Y-7.16.4, i.v.	neu-N transgenic mouse model with rat HER-2/neu expression and spontaneous lung metastases & NT2.5 mouse mammary fat pad xenografts with rat HER-2/neu.	225Ac-TAT had greater efficacy but with renal toxicity relative to 213Bi-TAT & 90Y-TBT.	[152]
225Ac, 213Bi	BD, efficacy, toxicity	nucleolin	F3 peptide	225Ac–DOTA–F3, 213Bi–DTPA–F3, i.p.	MDA-MB-435 human peritoneal carcinomatosis in SCID mice.	225Ac-TAT had greater efficacy relative to 213Bi-TAT with specific tumor uptake and minor renal toxicity.	[153,154]
225Ac	Vascular normalization & efficacy	Vascular endothelial (VE)-cadherin	E4G10 Ab	225Ac–DOTA–E4G10, i.v.	LS174T human colon s.c. xenografts in female nude mice.	Improved tumor vascular architecture & increased efficacy when combined with chemotherapy.	[107]
225Ac	Safety and efficacy	IL13RA2	Pep-1L peptide	[225Ac]Pep-1L, stereotactic intracranial injection	U8251 human glioblastoma orthotopic xenografts in male nude mice.	Efficacy with no significant toxicity.	[155]
225Ac	BBB and BTB permeabili-zation	Integrin αvβ3	small-molecule antagonist	225Ac-labeled targeted liposomes (225Ac-TL), intracranial injection	U87 MG human glioblastoma orthotopic xenografts in male nude mice.	Enhanced blood-brain barrier (BBB) and bood-tumor barrier (BTB) permeability.	[156]
225Ac	BD, Efficacy	Thrombo-modulin	201b mAb	LnPO4 nanoparticles (NPs) doped with 225Ac-201b, i.v.	Syngeneic EMT6 mouse breast epithelial cell metastases in BALB/c mouse lung following i.v. injection of cells	Retention of 225Ac and daughters in lung tissue, metastasis burden reduced.	[157]
225Ac	Micro BD, RD	PD-L1	anti-PD-L1-BC Ab	225Ac–DOTA–anti-PD-L1-BC, i.v.	NT2.5 mouse mammary xenografts in female nude mice.	Uniform distribution in liver, non-uniform in kidney and tumor, liver RD was limiting.	[158]
225Ac	BD and toxicity	Bone metastasis	Zoledronic acid (ZOL)	225Ac–DOTAZOL, i.v.	Wistar rats.	High bone:blood ratio. Kidney toxicity.	[159]
225Ac	BD, RD and dose response	PSMA	PSMA ligands with albumin-binding moiety	225Ac-RPS-074, i.v.	LNCaP human prostate cancer s.c. xenografts in BALB/c mice.	Decreased clearance rate, single administration had complete response in 86% of tumors.	[160]
225Ac	PK, BD, specificity, RD, toxicity, efficacy	MC1R	MC1RL peptide	225Ac–DOTA–MC1RL, i.v.	PK (Sprague-Dawley rats), BALB/c mice (toxicity and BD) and MEL270 human uveal melanoma s.c. xenografts in SCID mice (BD and efficacy).	Renal and hepatobiliary excretion, rapid blood clearance, low toxicity, prolonged survival and decreased metastasis after single injection.	[67]
225Ac	Efficacy, toxicity	CA19.9	5B1 human mAb	225Ac-labeled tetrazine radioligand and a transcyclooctene5B1 for pretargeting, i.v.	Bilateral MIAPaCa-2 (CA19.9-negative) and BxPC3 (CA19.9-positive) pancreatic cancer s.c. xenografts, and BxPC3 orthotopic xenografts in nude mice.	Pretargeting has similar efficacy compared to conventional TAT with reduced hematotoxicity.	[144]
211At	BD, RD, specificity, efficacy, toxicity	Tenascin glycoprotein	81C6 mAb	211At-81C6, subarachnoid catheter or i.v.	Female athymic rat model of neoplastic meningitis by inoculation of human rhabdomyosarcoma cells via subarachnoid catheter.	Efficacy without significant toxicity. RD estimates.	[161,162]
211At	PK, BD, efficacy, toxicity	gp38	MOv18 mAb	211At- & 131I-MOv18, i.p. or i.v.	Peritoneal OVCAR-3 human ovarian xenografts in BALB/c ν/ν or nude mice following IP injection of cells.	211At-TAT had greater efficacy relative to 131I-TBT.	[163,164,165,166]
211At	Tumor neo-vasculature targeting	Fibronectin ED-B domain	Human scFv(L19)	211At-scFv(L19), i.v.	Murine F9 teratocarcinoma & rat FE8 sarcoma in female nude mice.	Retained at tumor blood vessels resulting in increased tumor to blood ratios.	[140]
211At	BD, tumor dosimetry, efficacy, toxicity	95-kDa glycoprotein	MX35 mAb	211At-MX35, i.p. or i.v.	OVCAR-3 human ovarian cancer micrometastases in nude mice.	Fractionated treatment increased efficacy without significant toxicity.	[23,167,168]
211A, 90Y	Efficacy	CD30	HeFi-1 mAb	211At-, 90Y HeFi-1, i.v.	Human anaplastic large cell lymphoma cells in SCID/NOD mice. Karpas 299 cell i.v. injection for leukemia & SUDHL-1 xenografts for lymphoma.	211At-HeFi-1 increased survival in the leukemia model & combination with unlabeled HeFI-1 further improved efficacy. 90Y-HeFi-1 TBT increased survival in the lymphoma model.	[169]
211At	BD, efficacy, toxicity	CD44v6	U36 chimeric mAb	211At-U36, i.v.	UT-SCC7 human head and neck squamous cell carcinoma s.c. xenografts in nude mice.	Reduced tumor growth with no significant toxicity. BD consistent with targeting.	[170]
211At	BD, efficacy, toxicity	HER2/neu	C6.5 diabody	211At-SAPS-C6.5, i.v.	HER2/neu-positive MDA-MB-361/DYT2 breast xenografts in nude mice.	Tumor growth delay with low renal toxicity.	[142]
211At	Efficacy	NIS-transduced tumor cells	Astatide (HAt) peptide	211At-astatide, i.p.	NIS transduced LNCaP human prostate (NP-1) and parental (P-1) s.c. xenografts in male nude mice.	Accumulation similar to iodine with efficacy against NP-1 tumors relative to control P-1 tumors.	[147]
211At, 213Bi	BD, myelo suppression, toxicity	CD45	30F11 Ab	211At-30F11-ADTM, 213Bi-30F11-CHX-A″, i.v.	Female BALB/c mice.	211At-TAT induced myeloablation in haematopoietic tissues with greater efficacy and less toxicity relative to the 213Bi conjugate.	[171]
211At	Efficacy	HER-2/neu	Trastuzumab	211At-trastuzumab, i.p.	SKOV3 human ovarian i.p. xenografts in nude mice.	Combination of trastuzumab and 211At-trastuzumab resulted in complete tumor eradication.	[172]
211At	Dosimetry, toxicity, efficacy	Lewis Y epitope	BR96, chimeric IgG1 mAb	211At-BR96, i.v.	BN7005-H1D2 rat syngeneic sub-peritoneal colon engraftments.	Resulted in undetectable tumors with tolerable toxicity.	[173]
211At	Efficacy	CD20	1F5 mAb	211At-1F5, i.v.	Human Ramos (Burkitt lymphoma) s.c. xenografts in nude mice and i.v. injection of Ramos cells in SCID mice for disseminated lymphoma.	Highly effective in minimal residual disease mouse model.	[77]
211At	BD, dosimetry	Sigma-2 receptor	MM3 ligand	211At-MM3, i.v.	EMT6 murine breast syngeneic tumor in female BALB/c mice.	Tumor specific targeting.	[146]
211At	Efficacy	Norepineph-erine transporter	Benzyl-guanidine	meta-[211At]-astatobenzyl-guanidine, i.v.	PC12 rat pheochromocytoma s.c. xenograft in nude mice.	Reduced tumor size without weight loss.	[174]
211At	BD, efficacy	MICA/B	anti MICA/B Ab	211At-anti MICA/B Ab, i.v.	HCT116 (p53-/- & MICA/B positive) human colon cancer s.c. xenograft in nude mice.	Significant reduction in tumor growth, no weight loss, erythrocytopenia with recovery in 3-4 wks.	[175]
213Bi, 90Y	Toxicity and efficacy	CO17-1A	CO17-1A Fab’	213Bi-Fab’ and 90Y-Fab’, i.v.	GW-39 human colon cancer s.c. xenograft in nude mice.	TAT had greater efficacy and lower toxicity than TBT.	[176]
212Bi	Specificity, efficacy, toxicity	gp70	103A mAb	212Bi–CHX-A-DTPA–103A, i.v.	RLV induced erythroleukemia in BALB/c mice.	Clinical and histological remission of erythroleukemia and prolonged survival with low toxicity.	[177]
212Bi	BD, efficacy, toxicity	CD25	Anti-Tac, humanized mAb	2l2Bi–CHX-A-anti-Tac, i.v.	SP2 and SP2/Tac syngeneic murine lymphoma in nude mice.	Effective in treatment of bulky solid tumors.	[178]
213Bi	Stability, PK, toxicity	CD33	HuM195 mAb	213-Bi-CHX-A-DTPA–HuM195, i.p. or i.v.	Normal BALB/c mice without leukemia.	Favorable stability, PK and toxicity.	[179]
213Bi, 90Y	Pretargeting efficacy	CD25 (Tac)	Humanized anti-Tac mAb (HAT)	213Bi- & 90Y-DOTA–HAT; & HAT–streptavidin & 213Bi–DOTA–biotin or 90Y-DOTA–biotin, i.v.	Intraperitoneal MET-1 human adult T-cell leukemia in SCID/NOD mice.	Pre-targeted 213Bi TAT increased survival relative to 213Bi–DOTA–HAT, 90Y TBT & pre-targeted TBT.	[143]
213Bi, 131I	Efficacy	TAG-72	Humanized, domain-deleted CC49 mAb (HuCC49ΔCH2)	213Bi- or 131I-HuCC49ΔCH2, i.p.	TAG-72+ LS-174T & TAG-72 negative MIP human colon i.p. xenografts in nude mice.	213Bi-TAT had greater growth inhibition or regression relative to 131I-TBT.	[180]
213Bi	Efficacy, toxicity	d9-E-cad	d9-E-cad mAb	213Bi-d9-E-cad mAb, i.p.	HSC45-M2 human gastric i.p. xenografts with d9-E-cad mutation in female nude mice.	Double administration had greater efficacy relative to single administration, with no toxicity.	[181]
213Bi	BD, efficacy, toxicity	Somatostatin receptors	DOTATOC peptide	213Bi–DOTATOC, i.v.	CA20948 rat pancreatic adenocarcinoma tumors in Lewis rats.	Antitumor efficacy with low toxicity.	[64]
213Bi	Specificity, BD	CD87	P-P4D peptide	213Bi-P-P4D, i.p.	OV-MZ-6 human ovarian i.p. xenografts in female nude mice.	Specific tumor uptake, kidney uptake reduced by co-injection of gelofusine.	[182]
213Bi	Efficacy, toxicity	MUC1, uPAR and BLCA-38	C595 & BLCA-38 mAbs, & PAI2 protein	213Bi-C595, -BLCA-38 & -PAI2, i.p.	PC-3 human prostate orthotopic, intratibial and s.c. xenograft tumors in NOD SCID mice.	Multiple TAT can overcome heterogeneous antigen expression with efficacy against micrometastases.	[145]
213Bi	Efficacy, toxicity	EGFR	Matuzumab	213Bi-matuzumab, intravesical	EJ28 human orthotopic bladder xenografts in nude mice.	Increased survival without toxicity. Combination with mitomycin C increased efficacy with nephrotoxicity.	[183]
213Bi	Efficacy	TAG-72	Humanized CC49 mAb (HuCC49DCH2)	213Bi- HuCC49DCH2, i.p.	LS-174T human colon i.p. xenografts in female nude mice.	Combination trastuzumab and i.p. TAT increased efficacy and was well tolerated.	[184]
213Bi	Pretargeting efficacy	CD20	scFv-1F5-SA (streptavidin fusion protein)	1F5-SA & 213Bi–DOTA–biotin, i.v.	Ramos human lymphoma xenografts in nude mice.	Tumor regression and increased survival in mice with small tumors via pretargeting.	[141]
213Bi, 177Lu	BD, dosimetry, efficacy, toxicity	GRP	PESIN and AMBA peptides	177Lu–DOTA–PESIN, 213Bi–DOTA–PESIN, or 213Bi-AMBA, i.v.	PC-3 human prostate s.c. xenografts in female nude mice.	213Bi-TAT had greater efficacy compared to 177Lu-TBT. 213Bi–DOTA–PESIN had lower renal toxicity relative to 213Bi-AMBA.	[185]
213Bi, 177Lu	Efficacy	CD138	9E7.4 mAb	213Bi-9E7.4 and 177Lu-9E7.4, i.v.	5T33 murine multiple myeloma cell syngeneic i.v. injection into C57/BL6 mice.	213Bi-9E7.4 increased survival and cured 45%, 177Lu-9E7.4′ increased survival, no cures.	[186]
213Bi, 177Lu	Efficacy, toxicity	Mutant d9-E-cadherin	d9MAb	213Bi-d9Mab & 177Lu-d9Mab, i.p.	HSC45-M2 human gastric cancer cell i.p. injection in nude mice.	213Bi had comparable efficacy with lower toxicity.	[187]
213Bi	BD, efficacy, toxicity	CD138	Anti-mouse CD138 Ab	213Bi-CD138, i.v.	5T33 mouse multiple myeloma cell engraftment into syngeneic C57BL/KaLwRij mice.	Increased survival with only moderate and transient toxicity.	[188]
213Bi	Efficacy, toxicity	EGFR	Matuzumab	213Bi-matuzumab, intravesical.	EJ28 human orthotopic bladder xenografts in nude mice.	Increased survival with low toxicity.	[189]
213Bi	PK, efficacy, dosimetry, toxicity	SSTR2	DOTATATE peptide	213Bi–DOTATATE, i.v.	Neuroendocrine H69 human small cell lung carcinoma and CA20948 rat pancreatic s.c. xenografts in nude mice.	Effective in small and large tumors (both types), with dose limiting renal toxicity.	[66]
212Pb	Efficacy	HER-1	Cetuximab	212Pb-cetuximab, i.p.	ILS174T human colon i.p. xenografts in nude mice.	Extended survival and combined with gemcitabine & carboplatin increased efficacy.	[190]
212Pb	Efficacy	MC1R	DOTA-Re (Arg11)CCMSH peptide	212Pb[DOTA]–Re (Arg11)CCMSH, i.v.	B16/F1 murine melanoma syngeneic s.c. engraftments in C57BL/6 mice.	Tumor eradication at higher activities.	[191]
212Pb	Efficacy	HER-2 and CEA	Trastuzumab & 35A7	212Pb-trastuzumab & 212Pb-35A7, i.p.	A-431 HER-2 positive and CEA transfected vulvar squamous carcinoma cells i.p in nude mice.	Internalizing anti-HER2 labeled Ab had greater efficacy than non-internalizing anti-CEA labeled Ab.	[192]
212Pb	Efficacy, toxicity	HER-2/neu	Trastuzumab	212Pb-trastuzumab, i.p.	LS174T human colon & Shaw human pancreatic i.p. xenografts in nude mice.	Increased survival with low toxicity.	[193]
212Pb	Efficacy	HER-2/neu	Trastuzumab	212Pb-trastuzumab, i.p.	LS-174T human colon i.p. xenografts in nude mice.	Combination with gemcitabine increased survival.	[194]
212Pb	BD, efficacy	B7-H3	376.96 mAb	212Pb-376.96, i.p.	ES-2 or A2780cp20 human ovarian cancer cells i.p. into nude mice.	High peritoneal retention, tumor tissue accumulation & increased survival.	[195]
212Pb	BD, efficacy	B7-H3	376.96 mAb	212Pb-376.96, i.v.	Panc039 pancreatic cancer orthotopic xenografts in nude mice.	High tumor uptake & tumor growth inhibition.	[196]
212Pb	BD, efficacy	CSPG4	225.28 mAb	212Pb-225.28, i.v.	SUM159 & 2LMP human triple negative breast cancer (TNBC) orthotopic mammary fat pad xenografts in nude mice.	Dose-dependent growth inhibition.	[197]
212Pb	Administration route, toxicity, efficacy	EGFR	Panitumumab F(ab’)2 fragment	212Pb-panitumumab F(ab’)2, i.p. & i.v.	ILS-174T human colon i.p. xenografts in nude mice.	Increased survival with tolerated toxicity via i.p. or i.v. injection.	[198]
212Pb	Efficacy, combination therapy	MC1R	ee-cyclized α-MSH peptide	212Pb–DOTA–MC1L, BRAFi & HDACi	A2058 & MEWO human melanoma xenografts in nude mice.	Improved tumor response by combination therapy.	[69]
227Th	BD, efficacy, toxicity	CD20	Rituximab	227Th–DOTA–p-benzyl-rituximab, i.v.	BALB/c mice & Raji human B-cell lymphoma s.c. xenografts in nude mice.	Increased efficacy with managable toxicity.	[199]
227Th	BD, efficacy, toxicity	HER-2/neu	Trastuzumab	227Th–DOTA–trastuzumab, i.v.	SKBR-3 human breast cancer xenografts in nude mice.	Tumor growth inhibition with no toxicity.	[200]
227Th	BD, efficacy, toxicity	CD70	Anti-human CD70 mAb	CD70-TTC, i.v.	786-O human renal cancer s.c. xenografts in nude mice	Well tolerated with inhibition of tumor growth.	[201]
224Ra	Efficacy, toxicity	peritoneal metastases	Injection into peritoneum	224Ra-labeled calcium carbonate microparticles, i.p.	ES-2 and SKOV3 human ovarian cancer i.p. xenografts in nude mice.	Well tolerated with antitumor effect.	[202]