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

Dekempeneer Y, Keyaerts M, Krasniqi A, Puttemans J, Muyldermans S, Lahoutte T, D'huyvetter M, Devoogdt N - Expert Opin Biol Ther (2016)

Bottom Line: We review the importance of targeted alpha therapy (TAT) and focus on nanobodies as potential beneficial vehicles.In recent years, nanobodies have been evaluated intensively as unique antigen-specific vehicles for molecular imaging and TRNT.We expect that the efficient targeting capacity and fast clearance of nanobodies offer a high potential for TAT.

View Article: PubMed Central - PubMed

Affiliation: a Vrije Universiteit Brussel, In Vivo Cellular and Molecular Imaging , Brussels , Belgium.

ABSTRACT

Introduction: The combination of a targeted biomolecule that specifically defines the target and a radionuclide that delivers a cytotoxic payload offers a specific way to destroy cancer cells. Targeted radionuclide therapy (TRNT) aims to deliver cytotoxic radiation to cancer cells and causes minimal toxicity to surrounding healthy tissues. Recent advances using α-particle radiation emphasizes their potential to generate radiation in a highly localized and toxic manner because of their high level of ionization and short range in tissue.

Areas covered: We review the importance of targeted alpha therapy (TAT) and focus on nanobodies as potential beneficial vehicles. In recent years, nanobodies have been evaluated intensively as unique antigen-specific vehicles for molecular imaging and TRNT.

Expert opinion: We expect that the efficient targeting capacity and fast clearance of nanobodies offer a high potential for TAT. More particularly, we argue that the nanobodies' pharmacokinetic properties match perfectly with the interesting decay properties of the short-lived α-particle emitting radionuclides Astatine-211 and Bismuth-213 and offer an interesting treatment option particularly for micrometastatic cancer and residual disease.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of antibodies and their derived antigen-binding fragments. a. Conventional mAb and the derived Fab, scFv, Fv domains VL or VH, Fab’2, minibody and diabody. b. Camelid heavy-chain-only antibody and its VHH (also known as nanobody).
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Figure 0001: Schematic representation of antibodies and their derived antigen-binding fragments. a. Conventional mAb and the derived Fab, scFv, Fv domains VL or VH, Fab’2, minibody and diabody. b. Camelid heavy-chain-only antibody and its VHH (also known as nanobody).

Mentions: mAbs are Y-shaped proteins that contain two identical fragment antigen-binding (Fab) fragments and a fragment crystallizable (Fc) region (Figure 1). They are produced by plasma cells (mature, activated B cells) and are recruited by the immune system to identify and destroy foreign objects. Moreover, they have the capacity to bind any potential antigen epitope with high affinity, including tumor-associated biomarkers. Today, a variety of preclinical and clinical investigations were conducted using mAbs labeled with α-particle-emitting radionuclides (Table 2). The melanoma trials (Table 2) using 213Bi-cDTPA-9.2.27 show that solid tumors can be regressed by TAVAT. Moreover, these clinical results demonstrated that TAVAT for melanoma patients were locally efficacious and nontoxic up to 1.4 mCi. In the 213Bi-HuM195 phase I study described above, the authors provided a proof-of-concept for the use of α-particle immunotherapy to treat myeloid leukemia. Although 213Bi-HuM195 was well tolerated and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts, myelosuppression was seen in all treated patients.[28] Similarly, myelosuppression and liver function abnormalities were observed in a phase I/II trial investigating antileukemic effects of 213Bi-HuM195 after partial cytoreductive chemotherapy.[29] These toxicities could be explained by the suboptimal pharmacokinetic properties of mAbs as vehicles for TAT. The high molecular weight of mAbs (150 kDa) and the presence of an Fc-region result in a long serum half-life (several days or weeks) and in interactions with Fc-receptors in myeloid and hepatic sinusoidal cells, resulting in higher bone marrow toxicity and accumulation in the liver. Improvement in antibody engineering has led to the development of antibody fragments that are smaller and devoid of Fc, such as 25-kDa single-chain Fv (scFv), Fab (50 kDa), F(ab′)2 (110 kDa), diabodies (55 kDa), and minibodies (80 kDa) without compromising their affinity and specificity (Figure 1).[96] Smaller engineered mAb derivatives are more rapidly delivered to the tumor and mediate more effective tumor penetration. Because of their smaller size and lack of Fc, they are more rapidly cleared from the circulation, which is indirectly proportional to the level of kidney retention. Therefore, their administration results in fast tumor uptake with high tumor-to-background ratios. One study reported the successful conjugation of 213Bi to anti-HER2 C6.5 scFv and diabody molecules. However, a lack of tumor-specific therapeutic effect was shown, probably resulting from instability of the scFv and diabody molecules in vivo.[46] Here, it was concluded that the physical half-life of 45.6 min of 213Bi was too short to allow the systemically administered diabody to specifically localize in an established solid tumor. In a subsequent study, 211At was coupled to the stable N-succinimidyl-N-(4-[211At] astatophenethyl) succinamate and subsequently conjugated to the C6.5 diabody (Table 2).[58] Here, the somewhat longer physical half-life of 211At matches more closely to the rapid tumor targeting and rather fast systemic clearance of the C6.5 diabody. In the 211At-MX35 F(ab′)2 phase I trial, therapeutic doses were reached for the treatment of ovarian cancer.[55] However, 50% of the initial activity concentration of this radionuclide remained in the peritoneal fluids 24 h after injection, indicating a higher toxicity risk related to this immunoconjugate.Figure 1.


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

Dekempeneer Y, Keyaerts M, Krasniqi A, Puttemans J, Muyldermans S, Lahoutte T, D'huyvetter M, Devoogdt N - Expert Opin Biol Ther (2016)

Schematic representation of antibodies and their derived antigen-binding fragments. a. Conventional mAb and the derived Fab, scFv, Fv domains VL or VH, Fab’2, minibody and diabody. b. Camelid heavy-chain-only antibody and its VHH (also known as nanobody).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940885&req=5

Figure 0001: Schematic representation of antibodies and their derived antigen-binding fragments. a. Conventional mAb and the derived Fab, scFv, Fv domains VL or VH, Fab’2, minibody and diabody. b. Camelid heavy-chain-only antibody and its VHH (also known as nanobody).
Mentions: mAbs are Y-shaped proteins that contain two identical fragment antigen-binding (Fab) fragments and a fragment crystallizable (Fc) region (Figure 1). They are produced by plasma cells (mature, activated B cells) and are recruited by the immune system to identify and destroy foreign objects. Moreover, they have the capacity to bind any potential antigen epitope with high affinity, including tumor-associated biomarkers. Today, a variety of preclinical and clinical investigations were conducted using mAbs labeled with α-particle-emitting radionuclides (Table 2). The melanoma trials (Table 2) using 213Bi-cDTPA-9.2.27 show that solid tumors can be regressed by TAVAT. Moreover, these clinical results demonstrated that TAVAT for melanoma patients were locally efficacious and nontoxic up to 1.4 mCi. In the 213Bi-HuM195 phase I study described above, the authors provided a proof-of-concept for the use of α-particle immunotherapy to treat myeloid leukemia. Although 213Bi-HuM195 was well tolerated and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts, myelosuppression was seen in all treated patients.[28] Similarly, myelosuppression and liver function abnormalities were observed in a phase I/II trial investigating antileukemic effects of 213Bi-HuM195 after partial cytoreductive chemotherapy.[29] These toxicities could be explained by the suboptimal pharmacokinetic properties of mAbs as vehicles for TAT. The high molecular weight of mAbs (150 kDa) and the presence of an Fc-region result in a long serum half-life (several days or weeks) and in interactions with Fc-receptors in myeloid and hepatic sinusoidal cells, resulting in higher bone marrow toxicity and accumulation in the liver. Improvement in antibody engineering has led to the development of antibody fragments that are smaller and devoid of Fc, such as 25-kDa single-chain Fv (scFv), Fab (50 kDa), F(ab′)2 (110 kDa), diabodies (55 kDa), and minibodies (80 kDa) without compromising their affinity and specificity (Figure 1).[96] Smaller engineered mAb derivatives are more rapidly delivered to the tumor and mediate more effective tumor penetration. Because of their smaller size and lack of Fc, they are more rapidly cleared from the circulation, which is indirectly proportional to the level of kidney retention. Therefore, their administration results in fast tumor uptake with high tumor-to-background ratios. One study reported the successful conjugation of 213Bi to anti-HER2 C6.5 scFv and diabody molecules. However, a lack of tumor-specific therapeutic effect was shown, probably resulting from instability of the scFv and diabody molecules in vivo.[46] Here, it was concluded that the physical half-life of 45.6 min of 213Bi was too short to allow the systemically administered diabody to specifically localize in an established solid tumor. In a subsequent study, 211At was coupled to the stable N-succinimidyl-N-(4-[211At] astatophenethyl) succinamate and subsequently conjugated to the C6.5 diabody (Table 2).[58] Here, the somewhat longer physical half-life of 211At matches more closely to the rapid tumor targeting and rather fast systemic clearance of the C6.5 diabody. In the 211At-MX35 F(ab′)2 phase I trial, therapeutic doses were reached for the treatment of ovarian cancer.[55] However, 50% of the initial activity concentration of this radionuclide remained in the peritoneal fluids 24 h after injection, indicating a higher toxicity risk related to this immunoconjugate.Figure 1.

Bottom Line: We review the importance of targeted alpha therapy (TAT) and focus on nanobodies as potential beneficial vehicles.In recent years, nanobodies have been evaluated intensively as unique antigen-specific vehicles for molecular imaging and TRNT.We expect that the efficient targeting capacity and fast clearance of nanobodies offer a high potential for TAT.

View Article: PubMed Central - PubMed

Affiliation: a Vrije Universiteit Brussel, In Vivo Cellular and Molecular Imaging , Brussels , Belgium.

ABSTRACT

Introduction: The combination of a targeted biomolecule that specifically defines the target and a radionuclide that delivers a cytotoxic payload offers a specific way to destroy cancer cells. Targeted radionuclide therapy (TRNT) aims to deliver cytotoxic radiation to cancer cells and causes minimal toxicity to surrounding healthy tissues. Recent advances using α-particle radiation emphasizes their potential to generate radiation in a highly localized and toxic manner because of their high level of ionization and short range in tissue.

Areas covered: We review the importance of targeted alpha therapy (TAT) and focus on nanobodies as potential beneficial vehicles. In recent years, nanobodies have been evaluated intensively as unique antigen-specific vehicles for molecular imaging and TRNT.

Expert opinion: We expect that the efficient targeting capacity and fast clearance of nanobodies offer a high potential for TAT. More particularly, we argue that the nanobodies' pharmacokinetic properties match perfectly with the interesting decay properties of the short-lived α-particle emitting radionuclides Astatine-211 and Bismuth-213 and offer an interesting treatment option particularly for micrometastatic cancer and residual disease.

No MeSH data available.


Related in: MedlinePlus