| 1. |
- Machulkin, Aleksei E., et al.
(författare)
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Synthesis and Preclinical Evaluation of Urea-Based Prostate-Specific Membrane Antigen-Targeted Conjugates Labeled with 177Lu
- 2024
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Ingår i: ACS Pharmacology & Translational Science. - : American Chemical Society (ACS). - 2575-9108. ; 7:5, s. 1457-1473
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Tidskriftsartikel (refereegranskat)abstract
- 177Lu-labeled small-molecule prostate-specific membrane antigen (PSMA) targeted tracers are therapeutic agents for metastatic castration-resistant prostate cancer. Optimizing molecular design holds the potential to further enhance the pharmacokinetic properties of PSMA-targeted agents while preserving their potent therapeutic effects. In this study, six novel N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-l-lysine (DCL) urea-based PSMA ligand 2,2′,2″,2‴-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid conjugates were synthesized. These conjugates feature polypeptide linkers containing the Phe-Phe peptide sequence and an aromatic fragment at the ε-NH-Lys group of the DCL fragment. The synthesis yielded products with satisfactory yields ranging from 60% to 72%, paving the way for their preclinical evaluation. The labeling of the new variants of urea-based PSMA inhibitors provided a radiochemical yield of over 95%. The 177Lu-labeled conjugates demonstrated specific and moderate affinity binding to PSMA-expressing human cancer cells PC3-pip in vitro and specific accumulation in PSMA-expressing xenografts in vivo. Based on the results, both the lipophilicity and the type of substituent in the linker significantly influence the binding properties of the PSMA inhibitor and its biodistribution profile. Specifically, the studied variants containing a bromine substituent or a hydroxyl group introduced into the aromatic fragment of the phenylalanyl residue in DCL exhibit higher affinities to PSMA compared to variants with only a chlorine-substituted aromatic fragment or variants without any substituents. The [177Lu]Lu-13C with the bromine substituent was characterized by the highest activity accumulation in blood, salivary glands, muscle, bone, and gastrointestinal tract and had inasmuch as an unfavorable pharmacokinetic profile. The negative charge of the carboxyl group in the phenyl moiety of the [177Lu]Lu-13A variant has demonstrated a positive effect on reducing the retention of activity in the liver and the kidneys (the ratio of tumor to kidneys was 1.3-fold). Low accumulation in normal tissues in vivo indicates that this novel PSMA-targeting inhibitor is a promising radioligand.
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| 2. |
- Xu, Tianqi, et al.
(författare)
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Effect of Inter-Domain Linker Composition on Biodistribution of ABD-Fused Affibody-Drug Conjugates Targeting HER2
- 2022
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 14:3, s. 522-
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Tidskriftsartikel (refereegranskat)abstract
- Targeted drug conjugates based on Affibody molecules fused to an albumin-binding domain (ABD) for half-life extension have demonstrated potent anti-tumor activity in preclinical therapeutic studies. Furthermore, optimization of their molecular design might increase the cytotoxic effect on tumors and minimize systemic toxicity. This study aimed to investigate the influence of length and composition of a linker between the human epidermal growth factor receptor 2 (HER2)-targeted affibody molecule (Z(HER2:2891)) and the ABD domain on functionality and biodistribution of affibody-drug conjugates containing a microtubulin inhibitor mertansin (mcDM1) (AffiDCs). Two conjugates, having a trimeric (S(3)G)(3) linker or a trimeric (G(3)S)(3) linker were produced, radiolabeled with Tc-99m(CO)(3), and compared side-by-side in vitro and in vivo with the original Z(HER2:2891)-G(4)S-ABD-mcDM1 conjugate having a monomeric G(4)S linker. Both conjugates with longer linkers had a decreased affinity to HER2 and mouse and human serum albumin in vitro, however, no differences in blood retention were observed in NMRI mice up to 24 h post injection. The use of both (S(3)G)(3) and (G(3)S)(3) linkers reduced liver uptake of AffiDCs by approximately 1.2-fold compared with the use of a G(4)S linker. This finding provides important insights into the molecular design for the development of targeted drug conjugates with reduced hepatic uptake.
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| 3. |
- Yin, Wen, 1993-, et al.
(författare)
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A comparison of affibody conjugates loaded with auristatin and maytansine derived drugs
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Auristatin and maytansine-derived drugs are cytotoxic tubulin polymerization inhibitors commonly used as payloads in drug conjugates intended for targeted cancer therapy. We have previously shown that an affibody molecule ZHER2, binding to the human epidermal growth factor receptor 2 (HER2), can be site-specifically conjugated to DM1, a maytansine- derived payload, creating the potent and specific drug conjugate, ZHER2-ABD-mcDM1, where the ABD is an albumin binding domain used for in vivo half-life extension. Here, we investigated the properties of the HER2-binding affibody molecule conjugated with the two auristatin-derived payloads, monomethyl auristatin E and F (MMAE and MMAF), in comparison with the construct with DM1. We found that the drug conjugate ZHER2-ABD- mcMMAF was more potent than ZHER2-ABD-mcDM1, with IC50 values to high-HER2 expressing cell lines ranging from 0.18 to 12 nM. By contrast the IC50 values of ZHER2-ABD- mcMMAE was considerably weaker and this construct would probably benefit from a different linker connecting the drug to the affibody fusion protein. Quantification of uptake in HER2-expressing tumors and normal organs of 99m-technetium labeled drug conjugates showed that they were predominantly cleared by the kidneys, with relatively high tumor uptake, peaking at 11.1 ± 4.1 %ID/g for ZHER2-ABD-mcMMAE at 24 h post-injection, 8.5 ± 1.5 %ID/g for ZHER2-ABD-mcMMAF at 48 h post-injection, and 7.1 ± 1.8 %ID/g for ZHER2- ABD-mcDM1 at 48 h post-injection. Most normal organs, except for the kidneys, had a relatively low uptake. In conclusion, ZHER2-ABD-mcMMAF was the best performing drug conjugate with the highest potency, and lowest uptake in liver; slightly outperforming ZHER2- ABD-mcDM1.
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| 4. |
- Yin, Wen, 1993-, et al.
(författare)
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Comparison of HER2-targeted affibody conjugates loaded with auristatin-and maytansine-derived drugs
- 2023
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Ingår i: Journal of Controlled Release. - : Elsevier. - 0168-3659 .- 1873-4995. ; 355, s. 515-527
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Tidskriftsartikel (refereegranskat)abstract
- Treatment with antibody drug conjugates targeting receptors over-expressed on cancer cells is well established for clinical use in several types of cancer, however, resistance often occurs motivating the development of novel drugs. We have recently investigated a drug conjugate consisting of an affibody molecule targeting the human epidermal growth factor receptor 2 (HER2), fused to an albumin-binding domain (ABD) for half-life extension, loaded with the cytotoxic maytansine derivative DM1. In this study, we investigated the impact of the cytotoxic payload on binding properties, cytotoxicity and biodistribution by comparing DM1 with the auristatins MMAE and MMAF, as part of the drug conjugate. All constructs had specific and high affinity binding to HER2, human and mouse albumins with values in the low- to sub-nM range. ZHER2-ABD-mcMMAF demonstrated the most potent cytotoxic effect on several HER2-over-expressing cell lines. In an experimental therapy study, the MMAFbased conjugate provided complete tumor regression in 50% of BALB/c nu/nu mice bearing HER2-overexpressing SKOV3 tumors at a 2.9 mg/kg dose, while the same dose of ZHER2-ABD-mcDM1 provided only a moderate anti-tumor effect. A comparison with the non-targeting ZTaq-ABD-mcMMAF control demonstrated HER2-targeting specificity. In conclusion, a combination of potent cytotoxicity in vitro, with minimal uptake in normal organs in vivo, and efficient delivery to tumors provided a superior anti-tumor effect of ZHER2-ABDmcMMAF, while maintaining a favorable toxicity profile with no observed adverse effects.
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