Targeted alpha therapy using short-lived alpha-particles and the promise of nanobodies as targeting vehicle

Figures & data

Table 1. Main characteristics of the currently available α-particle-emitting radionuclides.

Isotope	Daughter isotopes*	Physical half-life	Maximum energy (keV)	Occurrence (%)	Associated emissions
^211At	–	7.2 h	5.867	α (41.8%)	α, γ, LEE
	^211Po	516 ms	7.450	α (100%)
^225Ac	–	10 days	5.830	α (100%)	α, γ, Auger, β^−
	^221Fr	4.9 min	6.341	α (100%)
	^217At	32.3 ms	7.069	α (99.98%)/β^− (0.01%)
	^213Bi	45.6 min	6.051	α (2.2%)/β^−(97.8%)
	^213Po	4.2 µs	8.377	α (100%)
^213Bi	–	45.6 min	6.051	α (2.2%)/β^− (97.8%)	α, γ, Auger, β^−
	^213Po	4.2 µs	8.377	α (100%)
^212Bi	–	61 min	5.870	α (36%)/β^− (64%)	α, γ, Auger, β^−
	^212Po	298 ns	8.785	α (100%)
^227Th	–	18.72 days	6.038	α (100%)	α, γ, Auger, β^−
	^223Ra	11.4 days	5.871	α (100%)
	^219Rn	4 s	6.819	α (100%)
	^215Po	1.8 ms	7.386	α (100%)
	^211Bi	2.14 min	6.623	α (99.7%)/β^− (0.3%)
^212Pb	–	10.64 h		β^− (100%)	β^−
	^212Bi	61 min	5.870	α (36%)/β^− (64%)	α, γ, Auger, β^−
	^212Po	0.3 μs	8.785	α (100%)
^223Ra	–	11.4 days	5.871	α (100%)	α, γ, Auger, β^−
	^219Rn	4 s	6.819	α (100%)
	^215Po	1.8 ms	7.386	α (100%)
	^211Bi	2.14 min	6.623	α (99.7%)/β^− (0.3%)

*Generated α-particle emitter after decay of the conjugated parent.

LEE: Low-energy electron emission; NS: yield not significant.

Table 2. Vehicles used in targeted α-particle therapy in preclinical and clinical settings.

Radionuclide	TAT agent	Indication	Antigen	Reference (preclinical data)	Reference (clinical phase)
^225Ac	Anti-CD33 IgG (HuM195)	Leukemia	CD33	[18]	I [19,20]
^225Ac	Anti-HER2 IgG (trastuzumab)	Ovarian cancer	HER2	[21]	–
^227Th	Anti-HER2 IgG (trastuzumab)	Breast and ovarian cancer	HER2	[22,23]
^227Th	Anti-CD20 IgG (rituximab)	Non-Hodgkin lymphoma	CD20	[24,25]
^213Bi	Anti-CD33 IgG (HuM195)	Leukemia	CD33	[26,27]	I and I/II [28,29]
^213Bi	Anti-CD20 IgG (rituximab)	Non-Hodgkin lymphoma	CD20	[30,31]	I [32]
^213Bi	Plasminogen activator inhibitor type 2	Breast cancer, pancreatic cancer	Urokinase plasminogen activator receptor	[33–35]
^213Bi	Anti‐MUC1 IgG (C595 IgG)	Ovarian cancer, pancreatic cancer	MUC1	[36,37]
^213Bi	Substance P	Glioblastoma	Neurokinin type-1 receptor		0/I [38,39]
^213Bi	Anti-NG2 IgG (9.2.27 IgG)	Melanoma	NG2 proteoglycan	[40,41]	I [15,42,43]
^213Bi	Anti-CD138 IgG	Multiple myeloma	CD138	[44]
^213Bi	Anti-PSMA IgG (J591 IgG)	Prostate cancer	PSMA	[45]
^213Bi	C6.5K-A scFv, C6.5K-A diabody	Breast and ovarian carcinomas	HER2	[46]
^212Pb/^212Bi	Anti-HER2 IgG (TCMC-trastuzumab)	Ovarian cancer	HER2	[47,48]	[48–50]
^211At	Chimeric 81C6 IgG	Glioblastoma	Tenascin-C	[51,52]	II [53]
^211At	MX35 F(ab′)2	Ovarian cancer	NaPi2b	[54]	I [55]
^211At	Anti-FRA IgG (Mov18)	Ovarian cancer	Folate receptor alpha	[56]
^211At	Anti-EGFRvIII IgG	Glioblastoma	EGFRvIII	[57]
^211At	Anti-HER2 C6.5 diabody	Breast cancer	HER2	[58]
^211At	ZHER2:342 and (ZHER2:4)2 affibody molecules	Breast and ovarian carcinomas	HER2	[59]
^223Ra	^223Ra-chloride	Skeletal breast and prostate cancer metastases	Hydroxyapatite	[60]	I–III [61,62]

NG2: Neural/glial antigen 2; PSMA: prostate-specific membrane antigen; EGFRvIII: epidermal growth factor receptor variant III.

Figure 1. Schematic representation of antibodies and their derived antigen-binding fragments. a. Conventional mAb and the derived Fab, scFv, Fv domains V_L or V_H, Fab’₂, minibody and diabody. b. Camelid heavy-chain-only antibody and its V_HH (also known as nanobody).

Figure 2. Nanobodies possess numerous advantageous characteristics, including their high antigen specificity (a) and high tumor targeting potential (b). a. ^99mTc-labeled-nanobody targeting the complement receptor of the Ig superfamily, CRIg, expressed on Kupffer cells in the liver. 3D-rendered SPECT/micro-CT images of naive wild-type (A.1.) and CRIg^−/− mice (A.2.) 1 h after intravenous injection of ^99mTc-labeled-nanobody. Representative images for 3 mice per group are shown. Figures adapted with permission from.[115] b. Dosimetry calculation of untagged ¹⁷⁷Lu-DTPA-anti-HER2 nanobody coinfused with 150 mg/kg Gelofusin, in HER2^pos tumor xenografted mice. Radiolabeling of nanobodies is characterized by significant retention of radioactivity at the kidneys, due to the charged-based aspecific tubular reuptake after glomerular filtration. Figure adapted with permission from.[109].

Figure 3. Diagnostic tumor imaging using ⁶⁸Ga-HER2-nanobody in patients with HER2^pos-breast cancer. a. Time-activity curve of total blood activity, expressed in % of injected activity (%IA) (n=20). b. Fusion PET/CT images of the uptake of ⁶⁸Ga-HER2-nanobody in breast carcinoma lesions. (B.1.) Patient with the highest tracer uptake (SUVmean 11.8) in a primary breast carcinoma. (B.2.) Patient with moderate tracer uptake in the left breast, which is easily discernable from background (SUVmean 4.9). (B.3.) Patient with invaded lymph nodes in the mediastinum and left hilar region. Lesions are indicated by red arrows. Figures are adapted with permission from.[110].

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