Antibody-drug conjugate (ADC) is typically composed of a monoclonal antibody (mAbs) covalently attached to a cytotoxic drug via a chemical linker. It combines both the advantages of highly specific targeting ability and highly potent killing effect to achieve accurate and efficient elimination of cancer cells, which has become one of the hotspots for the research and development of anticancer drugs. Since the first ADC, Mylotarg® (gemtuzumab ozogamicin), was approved in 2000 by the US Food and Drug Administration (FDA), there have been 14 ADCs received market approval so far worldwide. Moreover, over 100 ADC candidates have been investigated in clinical stages at present. This kind of new anti-cancer drugs, known as "biological missiles", is leading a new era of targeted cancer therapy. Herein, we conducted a review of the history and general mechanism of action of ADCs, and then briefly discussed the molecular aspects of key components of ADCs and the mechanisms by which these key factors influence the activities of ADCs. Moreover, we also reviewed the approved ADCs and other promising candidates in phase-3 clinical trials and discuss the current challenges and future perspectives for the development of next generations, which provide insights for the research and development of novel cancer therapeutics using ADCs. 

https://www.nature.com/articles/s41392-022-00947-7.pdf

Antibody drug conjugate: the “biological missile” for targeted cancer therapy

Second Version of the Prostate Cancer Molecular Imaging Standardized Evaluation Framework Including Response Evaluation for Clinical Trials (PROMISE V2).

Abstract Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [ 177 Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug. Preliminary data suggest that 177 Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&amp;T are currently being evaluated in ongoing phase 3 trials. The purpose of this guideline is to assist nuclear medicine personnel, to select patients with highest potential to benefit from 177 Lu-PSMA-RLT, to perform the procedure in accordance with current best practice, and to prepare for possible side effects and their clinical management. We also provide expert advice, to identify those clinical situations which may justify the off-label use of [ 177 Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis. 

https://link.springer.com/content/pdf/10.1007/s00259-023-06255-8.pdf

Joint EANM/SNMMI procedure guideline for the use of 177Lu-labeled PSMA-targeted radioligand-therapy (177Lu-PSMA-RLT)

Rationale: Lu-177-PSMA-617 radioligand therapy (RLT) is currently under approval for treatment of metastatic castration resistant prostate cancer (mCRPC) patients with late stage disease. However, previous studies demonstrated both heterogeneity of prostate specific membrane antigen (PSMA) expression, as well as response to PSMA treatment among mCRPC patients. Thus, there is an unmet need for identifying predictive parametres prior or under PSMA-RLT treatment. We therefore aimed to correlate several clinical and molecular parameters with response to PSMA treatment in a cohort of mCRPC patients undergoing PSMA RLT followed by a detailed analysis of promising candidates. Methods: Nineteen patients, median age 68.8 years (range: 56.9 - 83.3) with mCRPC were included in this study. We performed baseline analysis of clinical parameters based on PSMA PET/CT, (metabolic tumor volume (MTV), total tumor volume (TTV)), serum PSA, ALP, LDH and gene expression analysis of circulating tumor cells (expression of AR full length (AR-FL), AR splice variant 7 (AR-V7), PSA and PSMA) as well as common markers for neuroendocrine differentiation (NED). Results: Patients presented with bone, lymph node, and visceral metastases (89%, 68%, and 21%, respectively). All patients were pretreated with docetaxel, either abiraterone or enzalutamide, or both. Biochemical response in terms of PSA decline ≥50 or ≥30% was observed in 42% and 63%, respectively. There were significant correlations between PSA and PSMA mRNA expression, as well as tumor volumes (both MTV and TTV), AR-FL and AR-V7 mRNA expression. However, there was no correlation with response to PSMA treatment. Furthermore, none of these parameters was significantly correlated with baseline serum PSA values. Common NED markers were shown to be specifically high expressed and revealed impact on OS independent from AR-V7 gene expression. Conclusion: We demonstrate that AR-FL and its splice variant AR-V7 might serve as prognostic biomarkers displaying high tumor burden in mCRPC patient prior to PSMA-RLT. Contrary, PSMA, which has been discussed as a biomarker for PSMA targeted treatment, does not display strong prognostic ability - at least on the mRNA level. Surprisingly, none of these parameters correlates to response to PSMA treatment. In contrast, commom NED markers such as SYP and ENO2 as well as FOXA1 expression level seem to predict OS, but not PFS, more reliably. We admit that a limitation of our study is the focus on mRNA expression of potential biomarkers only. Further investigations analyzing the potential role of protein expression of these markers are therefore warranted.

Molecular analysis of circulating tumor cells of metastatic castration-resistant Prostate Cancer Patients receiving 177Lu-PSMA-617 Radioligand Therapy.

Prostate-specific membrane antigen (PSMA) targeted radiopharmaceutical therapy is a new treatment option for patients with advanced prostate cancer refractory to other treatments. Previously we synthesized a β-particle-emitting low-molecular-weight compound, 177Lu-L1, which demonstrated reduced off-target effects in a xenograft model of prostate cancer. Here we leveraged that scaffold to synthesize α-particle-emitting analogs of L1, 213Bi-L1, and 225Ac-L1 to evaluate their safety and cell kill effect in PSMA+ xenograft models.

Methods: Radiochemical synthesis, cell uptake, cell kill effect, and biodistribution of 213Bi-L1 and 225Ac-L1 were evaluated. The efficacy of 225Ac-L1 was determined in human PSMA+ subcutaneous and micrometastatic models. Subacute toxicity at 8 weeks and chronic toxicity at one year after administration were evaluated for 225Ac-L1. Radiation absorbed dose of 225Ac-L1 was determined using the biodistribution data and α-camera imaging.

Results:213Bi-/225Ac-L1 demonstrated specific cell uptake and cell kill in PSMA+ cells. Biodistribution of 213Bi-L1 and 225Ac-L1 revealed specific uptake of radioactivity within PSMA+ lesions. Treatment studies of 225Ac-L1 demonstrated activity-dependent, specific inhibition of tumor growth in the PSMA+ flank tumor model. 225Ac-L1 also showed an increased survival benefit in the micrometastatic model compared to 177Lu-L1. Activity-escalated acute and chronic toxicity studies of 225Ac-L1 revealed off-target radiotoxicity, mainly in kidneys and liver. The estimated maximum tolerated activity was ~1 MBq/kg. α-camera imaging of 225Ac-L1 revealed high renal cortical accumulation at 2 h followed by fast clearance at 24 h.

Conclusion:225Ac-L1 demonstrated activity-dependent efficacy with minimal treatment-related organ radiotoxicity issues. 225Ac-L1 is a promising therapeutic for further clinical evaluation.

https://jnm.snmjournals.org/content/jnumed/early/2020/12/04/jnumed.120.256388.full.pdf

Preclinical Evaluation of 213Bi- and 225Ac-Labeled Low-Molecular-Weight Compounds for Radiopharmaceutical Therapy of Prostate Cancer.

After years of development and many published studies, prostate-specificmembrane antigen–targeted radioligand therapy recently reached a critical milestone on March 23, 2022, with approval of Lu-PSMA-617 by the U.S. Food and Drug Administration (1). This landmark success heralds a new era of large-scale theranostics for nuclear medicine. This editorial provides the first-hand perspective on the origins of the phase III VISION trial and, specifically, the creation of the imaging criteria for selection of patients for PSMAtargeted therapy.

https://jnm.snmjournals.org/content/jnumed/63/6/816.full.pdf

Why We Did What We Did: PSMA PET/CT Selection Criteria for the VISION Trial

Visual Abstract Monitoring therapy response in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with novel hormonal therapies, taxanes, and newly approved therapies is crucial for optimizing treatment. [68Ga]Ga-prostate-specific membrane antigen (PSMA)-11 positron emission tomography/computed tomography (PSMA PET/CT) is a promising target for managing treatment in patients with prostate cancer. PSMA is overexpressed in patients with mCRPC; understanding how expression might change in patients undergoing treatment could determine its potential for guiding clinical decisions. We examined PSMA expression in patients with CRPC and compared PET/CT response with prostate-specific antigen (PSA) variation as a prognostic factor for progression-free survival and overall survival (PFS and OS, respectively). Methods: This was a single-center, retrospective observational cohort study in patients with CRPC enrolled in the PSMA-PROSTATA registry study (EudraCT: 2015-004589-27). A first and second (if applicable) PSMA PET/CT were performed to determine PSMA expression (absence or presence). PET/CT response was assessed as responders (patients with stable disease, partial or complete response) versus nonresponders (patients with progressive disease) by comparing the first with the second PET/CT. PSA variation (increase or decrease from baseline) was assessed across the same time period. PFS was defined as the time between second PET/CT and PSA recurrence or evidence of radiologic progression. Results: Overall, 160 patients with CRPC were included in the analysis. At first PET/CT, nearly all (n = 152; 95.0%) patients had PSMA expression (classified as mCRPC), irrespective of prior systemic therapy. SUVmax was positively associated with baseline PSA levels and velocity (both P < 0.001). According to PET/CT response, median SUVmax on first PET/CT was numerically lower in nonresponders than in responders (17.5 vs. 20.4; P = 0.127). Similarly, patients with a PSA increase had significantly lower median SUVmax on first PET/CT (15.8) than did those with a PSA decrease (30.4; P = 0.018). PSA change was, on average, 146% in nonresponders and −57% in responders between first and second PET/CT (P < 0.001). Agreement between PET/CT and PSA response was 79% (k = 0.553, P < 0.001). Among the 63 patients included in PFS/OS analyses, 76.2% had a relapse and 36.5% died before 24-mo follow-up; median PFS and OS were 6.1 and 24 mo, respectively. PET/CT response, independent of PSA variation, was a significant prognostic factor for PFS. OS was not significantly different between PET/CT responders and nonresponders. Conclusion: PSMA PET/CT may be a useful imaging method predictive of treatment response in patients with mCRPC, regardless of ongoing systemic therapy. Data also suggest that response assessed by PET/CT is a potentially more significant prognostic factor than PSA for PFS. Further studies are needed to understand the potential involvement of PSMA expression on survival.

/pdf/prostate-specific-membrane-antigen-expression-on-pet-ct-in-22xzj6y2.pdf

Prostate-Specific Membrane Antigen Expression on PET/CT in Patients with Metastatic Castration-Resistant Prostate Cancer: A Retrospective Observational Study

793PDPhase 1 study of the PSMA-targeted small-molecule drug conjugate EC1169 in patients with metastatic castrate-resistant prostate cancer (mCRPC)

CTC-based biomarkers & PSMA-targeted imaging in patients with metastatic castrate-resistant prostate cancer (mCRPC)

25 Rationale: Monitoring therapy response in patients with metastatic castration-resistant prostate 26 cancer ([m]CRPC) treated with novel hormonal therapies, taxanes and newly approved therapies is 27 crucial for optimizing treatment. [ 68 Ga]Ga-prostate-specific membrane antigen (PSMA)-11 positron 28 emission tomography/computed tomography (PSMA PET/CT) is a promising target for managing 29 treatment in patients with prostate cancer. PSMA is overexpressed in patients with mCRPC; 30 understanding how expression might change in patients undergoing treatment could determine its 31 potential for guiding clinical decisions. We examined PSMA expression in patients with CRPC and 32 compared PET/CT response with prostate-specific antigen (PSA) variation as prognostic factor for 33 progression-free and overall survival (PFS and OS). Methods: Single-centre, retrospective observational 34 cohort study in patients with CRPC enrolled in the PSMA-PROSTATA registry study (EudraCT: 2015- 35 004589-27). First and second (if applicable) PSMA PET/CT were performed to determine PSMA 36 expression (absence/presence). PET/CT response was assessed as responders (patients with stable 37 disease, partial or complete response) versus non-responders (patients with progressive disease) 38 comparing the first with the second PET/CT PET/CT. PSA variation (increase/decrease from baseline) 39 was assessed across the same time period. PFS was defined as time between second PET/CT and PSA 40 recurrence or evidence of radiological progression. Results: Overall, 160 patients with CRPC were 41 included in the analysis. At first PET/CT, nearly all (n=152; 95.0%) patients had PSMA expression 42 (classified as mCRPC), irrespective of prior systemic therapy. Maximized standardized uptake value 43 (SUV max ) was positively associated with baseline PSA levels and velocity (both P <0.001). According to 44 PET/CT response, median SUV max on first PET/CT was numerically lower in non-responders versus 45 responders (17.5 vs 20.4; P =0.127). Similarly, patients with a PSA increase had significantly lower

Prostate-Specific Membrane Antigen Expression on Positron 1 Emission Tomography/Computed Tomography in Patients with 2 Metastatic Castration-Resistant Prostate Cancer: A Retrospective 3 Observational Study

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