PSMA theragnostics for metastatic castration resistant prostate cancer

Song, Hong; Guja, Kip E.; Iagaru, Andrei

doi:10.1016/j.tranon.2022.101438

Cited by 8 publications

(6 citation statements)

References 93 publications

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“…111 In-capromab is a conjugated murine IgG1 mAb (7E11-C5.3) that targets a PSMA epitope located in the intracellular domain 40,41 . 111 In-capromab pendetide was used to detect pelvic lymph node metastases in newly diagnosed high-risk prostate cancer patients and in the biochemical recurrence setting 42,43 . The first PSMA-targeted therapeutic radiopharmaceutical, yttrium-90 ( 90 Y)–labeled capromab pendetide, was associated with significant hematologic toxicity 44 .…”

Section: Cd20 As a Targetmentioning

confidence: 99%

“…40,41 111 Incapromab pendetide was used to detect pelvic lymph node metastases in newly diagnosed high-risk prostate cancer patients and in the biochemical recurrence setting. 42,43 The first PSMA-targeted therapeutic radiopharmaceutical, yttrium-90 ( 90 Y)-labeled capromab pendetide, was associated with significant hematologic toxicity. 44 It appears that 111 In/ 90 Y-capromab pendetide is fundamentally flawed due to its targeting of the intracellular domain of PSMA, which binds only dead or dying cells but not viable cancer cells.…”

Section: Psma As a Targetmentioning

confidence: 99%

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The Role of Radiolabeled Monoclonal Antibodies in Cancer Imaging and ADC Treatment

Martiniova¹,

Zieliński²,

Lin³

et al. 2022

Cancer J

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Antibody-drug conjugates (ADCs) are designed to deliver cytotoxic payloads to distinctive target-expressing cancer cells. Following internalization, the ADCs are routed to different compartments in the cells, where cleavage of the linker causes release of the cytotoxic cargo. With such a delivery system, more effective payloads can reach cancer cells, allowing for more efficient treatment and dosing schedule. The monoclonal antibody (mAb) component of ADC plays a crucial role in the effective targeting of cancer cell-specific antigens while minimizing binding to normal cells. Often, the same mAbs used in ADCs can be labeled instead with radionuclides suitable for positron emission tomography or gamma-camera scintigraphy. To achieve high sensitivity and specificity for imaging, radiolabeled mAbs must have high affinity for the antigen, favorable pharmacokinetic properties, and a low toxicity profile. The use of radiolabeled mAbs permits the noninvasive interrogation of specific target expression on tumor cells and assessment of tumor heterogeneity in vivo by a simple diagnostic imaging scan that may include the whole body in the field of view. With this approach, radiolabeled mAbs can serve as important imaging biomarkers to predict the optimal delivery of ADCs to tumors and be used to monitor therapy with follow-up scans. Moreover, the same mAb can then be radiolabeled with an analogous radionuclide for the delivery of β-emitters, α-particles, or Auger electrons as part of a radioimmunotherapy approach. The purpose of this review is to introduce key concepts regarding radiolabeled mAbs targeting various tumor antigens (CD20, CDH3, type I insulinlike growth factor receptor, prostate-specific membrane antigen, and human epidermal growth factor receptor 2) that are being used in the clinical setting or undergoing development.

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Section: Cd20 As a Targetmentioning

confidence: 99%

Section: Psma As a Targetmentioning

confidence: 99%

The Role of Radiolabeled Monoclonal Antibodies in Cancer Imaging and ADC Treatment

Martiniova¹,

Zieliński²,

Lin³

et al. 2022

Cancer J

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“…To date, intensive efforts are focused on targeting prostate-specific membrane antigen (PSMA) with radiotherapeutic agents. − PSMA is a zinc-protease enzyme (folate hydrolase I (FOLH1)) and receptor (glutamate carboxypeptidase II (GCPII)) endogenously expressed to a small extent in healthy human tissues and organs, including prostate epithelium, small intestine, neurogenic crypt cells, epididymis, ovary, salivary glands, and proximal renal tubules. − However, PSMA exhibits remarkably elevated expression levels up to 1000-fold higher than its constitutive expressionin the secretory acinar epithelium of prostate carcinoma. , This elevated expression is particularly pronounced in higher-grade cancers, metastatic forms, and hormone-resistant prostate carcinoma. Consequently, PSMA emerges as a crucial target for theranostic tracers in human prostate cancer.…”

mentioning

confidence: 99%

Synthesis and Preclinical Evaluation of Urea-Based Prostate-Specific Membrane Antigen-Targeted Conjugates Labeled with ¹⁷⁷Lu

Machulkin,

Petrov,

Bodenko

et al. 2024

ACS Pharmacol. Transl. Sci.

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177 Lu-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 ureabased PSMA inhibitors provided a radiochemical yield of over 95%. The 177 Lu-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 [ 177 Lu]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 [ 177 Lu]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 PSMAtargeting inhibitor is a promising radioligand.

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“…ADT, androgen deprivation therapy; FDG, fluorodeoxyglucose F 18; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen; SUV, standardized uptake value. Adapted fromSong et al 2022.…”

mentioning

confidence: 99%

PSMA-Directed Theragnostics: Transforming Prostate Cancer Landscape

2023

healthbook TIMES Onco Hema

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PSMA theragnostics for metastatic castration resistant prostate cancer

Cited by 8 publications

References 93 publications

The Role of Radiolabeled Monoclonal Antibodies in Cancer Imaging and ADC Treatment

The Role of Radiolabeled Monoclonal Antibodies in Cancer Imaging and ADC Treatment

Synthesis and Preclinical Evaluation of Urea-Based Prostate-Specific Membrane Antigen-Targeted Conjugates Labeled with ¹⁷⁷Lu

PSMA-Directed Theragnostics: Transforming Prostate Cancer Landscape

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PSMA theragnostics for metastatic castration resistant prostate cancer

Cited by 8 publications

References 93 publications

The Role of Radiolabeled Monoclonal Antibodies in Cancer Imaging and ADC Treatment

The Role of Radiolabeled Monoclonal Antibodies in Cancer Imaging and ADC Treatment

Synthesis and Preclinical Evaluation of Urea-Based Prostate-Specific Membrane Antigen-Targeted Conjugates Labeled with 177Lu

PSMA-Directed Theragnostics: Transforming Prostate Cancer Landscape

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Product

Resources

About

Synthesis and Preclinical Evaluation of Urea-Based Prostate-Specific Membrane Antigen-Targeted Conjugates Labeled with ¹⁷⁷Lu