Leveraging TROP2 Antibody-Drug Conjugates in Solid Tumors.

Antibody-drug conjugates (ADCs) have become the cornerstone of effective therapeutics in solid and hematological malignancies by harnessing potent cytotoxic payloads with targeted tumoricidal delivery. Since the monumental shift occurred with HER2-targeted ADCs, the discovery of the TROP2 antigen has revolutionized the landscape of ADC development. Moving beyond the traditional ADC design, multiple novel ADCs have successfully shaped and improved survival outcomes in patients with various tumor histologies. Here we review and contrast the clinical impact of the well-known TROP2 ADCs currently in clinical use. We also shed light on upcoming investigational TROP2 ADCs showing promise with novel ADC platforms.

Anti-CD45 PBD-based antibody-drug conjugates are effective targeted conditioning agents for gene therapy and stem cell transplant.

Stem cell gene therapy and hematopoietic stem cell transplantation (SCT) require conditioning to ablate the recipient's hematopoietic stem cells (HSCs) and create a niche for gene-corrected/donor HSCs. Conventional conditioning agents are non-specific, leading to off-target toxicities and resulting in significant morbidity and mortality. We developed tissue-specific anti-human CD45 antibody-drug conjugates (ADCs), using rat IgG2b anti-human CD45 antibody clones YTH24.5 and YTH54.12, conjugated to cytotoxic pyrrolobenzodiazepine (PBD) dimer payloads with cleavable (SG3249) or non-cleavable (SG3376) linkers. In vitro, these ADCs internalized to lysosomes for drug release, resulting in potent and specific killing of human CD45+ cells. In humanized NSG mice, the ADCs completely ablated human HSCs without toxicity to non-hematopoietic tissues, enabling successful engraftment of gene-modified autologous and allogeneic human HSCs. The ADCs also delayed leukemia onset and improved survival in CD45+ tumor models. These data provide proof of concept that conditioning with anti-human CD45-PBD ADCs allows engraftment of donor/gene-corrected HSCs with minimal toxicity to non-hematopoietic tissues. Our anti-CD45-PBDs or similar agents could potentially shift the paradigm in transplantation medicine that intensive chemo/radiotherapy is required for HSC engraftment after gene therapy and allogeneic SCT. Targeted conditioning both improve the safety and minimize late effects of these procedures, which would greatly increase their applicability.

Spotlight on ideal target antigens and resistance in antibody-drug conjugates: Strategies for competitive advancement.

Antibody-drug conjugates (ADCs) represent a novel and promising approach in targeted therapy, uniting the specificity of antibodies that recognize specific antigens with payloads, all connected by the stable linker. These conjugates combine the best targeted and cytotoxic therapies, offering the killing effect of precisely targeting specific antigens and the potent cell-killing power of small molecule drugs. The targeted approach minimizes the off-target toxicities associated with the payloads and broadens the therapeutic window, enhancing the efficacy and safety profile of cancer treatments. Within precision oncology, ADCs have garnered significant attention as a cutting-edge research area and have been approved to treat a range of malignant tumors. Correspondingly, the issue of resistance to ADCs has gradually come to the fore. Any dysfunction in the steps leading to the ADCs' action within tumor cells can lead to the development of resistance. A deeper understanding of resistance mechanisms may be crucial for developing novel ADCs and exploring combination therapy strategies, which could further enhance the clinical efficacy of ADCs in cancer treatment. This review outlines the brief historical development and mechanism of ADCs and discusses the impact of their key components on the activity of ADCs. Furthermore, it provides a detailed account of the application of ADCs with various target antigens in cancer therapy, the categorization of potential resistance mechanisms, and the current state of combination therapies. Looking forward, breakthroughs in overcoming technical barriers, selecting differentiated target antigens, and enhancing resistance management and combination therapy strategies will broaden the therapeutic indications for ADCs. These progresses are anticipated to advance cancer treatment and yield benefits for patients.

Tumor-targeted delivery of a STING agonist improvescancer immunotherapy.

The cGAS-STING pathway is essential for immune defense against microbial pathogens and malignant cells; as such, STING is an attractive target for cancer immunotherapy. However, systemic administration of STING agonists poses safety issues while intratumoral injection is limited by tumor accessibility. Here, we generated antibody-drug conjugates (ADCs) by conjugating a STING agonist through a cleavable linker to antibodies targeting tumor cells. Systemic administration of these ADCs was well tolerated and exhibited potent antitumor efficacy in syngeneic mouse tumor models. The STING ADC further synergized with an anti-PD-L1 antibody to achieve superior antitumor efficacy. The STING ADC promoted multiple aspects of innate and adaptive antitumor immune responses, including activation of dendritic cells, T cells, natural killer cells and natural killer T cells, as well as promotion of M2 to M1 polarization of tumor-associated macrophages. These results provided the proof of concept for clinical development of the STING ADCs.

Transplantation after CD45-ADC corrects Rag1 immunodeficiency in congenic and haploidentical settings.

BACKGROUND: Mutations in the recombinase-activating genes 1 and 2 (RAG1, RAG2) cause a spectrum of phenotypes, ranging from severe combined immune deficiency to combined immune deficiency with immune dysregulation (CID-ID). Hematopoietic cell transplantation is a curative option. Use of conditioning facilitates robust and durable stem cell engraftment and immune reconstitution but may cause toxicity. Transplantation from haploidentical donors is associated with poor outcome in patients with CID-ID. OBJECTIVES: We sought to evaluate multilineage engraftment and immune reconstitution after conditioning with CD45-antibody drug conjugate (CD45-ADC) as a single agent in hypomorphic mice with Rag1 mutation treated with congenic and haploidentical hematopoietic cell transplantation. METHODS: Rag1-F971L mice, a model of CID-ID, were conditioned with various doses of CD45-ADC, total body irradiation, or isotype-ADC, and then given transplants of total bone marrow cells from congenic or haploidentical donors. Flow cytometry was used to assess chimerism and immune reconstitution. Histology was used to document reconstitution of thymic architecture. RESULTS: Conditioning with CD45-ADC as a single agent allowed robust engraftment and immune reconstitution, with restoration of thymus, bone marrow, and peripheral compartments. The optimal doses of CD45-ADC were 1.5 mg/kg and 5 mg/kg for congenic and haploidentical transplantation, respectively. No graft-versus-host disease was observed. CONCLUSIONS: Conditioning with CD45-ADC alone allows full donor chimerism and immune reconstitution in Rag1 hypomorphic mice even following haploidentical transplantation, opening the way for the implementation of similar approaches in humans.

Based on PI-RADS v2.1 combining PHI and ADC values to guide prostate biopsy in patients with PSA 4-20 ng/mL.

PURPOSE: The study aimed to investigate the diagnostic accuracy of prostate health index (PHI) and apparent diffusion coefficient (ADC) values in predicting prostate cancer (PCa) and construct a nomogram for the prediction of PCa and clinically significant PCa (CSPCa) in Prostate Imaging-Reporting and Data System (PI-RADS) three lesions cohort. METHODS: This study prospectively enrolled 301 patients who underwent multiparametric magnetic resonance (mpMRI) and were scheduled for prostate biopsy. The receiver operating characteristic curve (ROC) was performed to estimate the diagnostic accuracy of each predictor. Univariable and multivariable logistic regression analysis was conducted to ascertain hidden risk factors and constructed nomograms in PI-RADS three lesions cohort. RESULTS: In the whole cohort, the area under the ROC curve (AUC) of PHI is relatively high, which is 0.779. As radiographic parameters, the AUC of PI-RADS and ADC values was 0.702 and 0.756, respectively. The utilization of PHI and ADC values either individually or in combination significantly improved the diagnostic accuracy of the basic model. In PI-RADS three lesions cohort, the AUC for PCa was 0.817 in the training cohort and 0.904 in the validation cohort. The AUC for CSPCa was 0.856 in the training cohort and 0.871 in the validation cohort. When applying the nomogram for predicting PCa, 50.0% of biopsies could be saved, supplemented by 6.9% of CSPCa being missed. CONCLUSION: PHI and ADC values can be used as predictors of CSPCa. The nomogram included PHI, ADC values and other clinical predictors demonstrated an enhanced capability in detecting PCa and CSPCa within PI-RADS three lesions cohort.

Response-guided neoadjuvant sacituzumab govitecan for localized triple-negative breast cancer: results from the NeoSTAR trial.

BACKGROUND: Sacituzumab govitecan (SG), a novel antibody-drug conjugate (ADC) targeting TROP2, is approved for pre-treated metastatic triple-negative breast cancer (mTNBC). We conducted an investigator-initiated clinical trial evaluating neoadjuvant (NA) SG (NCT04230109), and report primary results. PATIENTS AND METHODS: Participants with early-stage TNBC received NA SG for four cycles. The primary objective was to assess pathological complete response (pCR) rate in breast and lymph nodes (ypT0/isN0) to SG. Secondary objectives included overall response rate (ORR), safety, event-free survival (EFS), and predictive biomarkers. A response-guided approach was utilized, and subsequent systemic therapy decisions were at the discretion of the treating physician. RESULTS: From July 2020 to August 2021, 50 participants were enrolled (median age = 48.5 years; 13 clinical stage I disease, 26 stage II, 11 stage III). Forty-nine (98%) completed four cycles of SG. Overall, the pCR rate with SG alone was 30% [n = 15, 95% confidence interval (CI) 18% to 45%]. The ORR per RECIST V1.1 after SG alone was 64% (n = 32/50, 95% CI 77% to 98%). Higher Ki-67 and tumor-infiltrating lymphocytes (TILs) were predictive of pCR to SG (P = 0.007 for Ki-67 and 0.002 for TILs), while baseline TROP2 expression was not (P = 0.440). Common adverse events were nausea (82%), fatigue (76%), alopecia (76%), neutropenia (44%), and rash (48%). With a median follow-up time of 18.9 months (95% CI 16.3-21.9 months), the 2-year EFS for all participants was 95%. Among participants with a pCR with SG (n = 15), the 2-year EFS was 100%. CONCLUSIONS: In the first NA trial with an ADC in localized TNBC, SG demonstrated single-agent efficacy and feasibility of response-guided escalation/de-escalation. Further research on optimal duration of SG as well as NA combination strategies, including immunotherapy, are needed.

Ab initio investigation of excited state charge transfer pathways in differently capped bithiophene cages.

The electronic excitations of conformationally constrained bithiophene cage systems as previously investigated by Lewis et al. (J. Am. Chem. Soc. 143, 18548 (2021)) are revisited, employing the correlated ab initio Scaled Opposite-Spin Algebraic Diagrammatic Construction Second Order electronic structure method. Quantitative descriptors are determined to assess the extent of charge transfer between the bithiophene moieties and the capping domains, represented by either phenyl or triazine groups. The investigation substantiates intrinsic differences in the photophysical behavior of these two structural variants and reveals the presence of lower-energy excited states characterized by noteworthy charge transfer contributions in the triazine cage system. The manifestation of this charge transfer character is discernible even at the Franck-Condon geometry, persisting throughout the relaxation of the excited state. By examining isolated monomer building blocks, we confirm the existence of analogous charge transfer contributions in their excitations. Employing this methodological approach facilitates the prospective identification of potential wall/cap chromophore pairs, wherein charge transfer pathways can be accessed within the energetically favorable regime.

Interpretation of molecular electron transport in ab initio many-electron framework incorporating zero-point nuclear motion effects.

A computational methodology, founded on chemical concepts, is presented for interpreting the role of nuclear motion in the electron transport through single-molecule junctions (SMJ) using many-electron ab initio quantum chemical calculations. Within this approach the many-electron states of the system, computed at the SOS-ADC(2) level, are followed along the individual normal modes of the encapsulated molecules. The inspection of the changes in the partial charge distribution of the many-electron states allows the quantification of the electron transport and the estimation of transmission probabilities. This analysis improves the understanding of the relationship between internal motions and electron transport. Two SMJ model systems are studied for validation purposes, constructed from a conductor (BDA, benzene-1,4-diamine) and an insulator molecule (DABCO, 1,4-diazabicyclo[2.2.2]octane). The trends of the resulting transmission probabilities are in agreement with the experimental observations, demonstrating the capability of the approach to distinguish between conductor and insulator type systems, thereby offering a straightforward and cost-effective tool for such classifications via quantum chemical calculations.

An immunomodulatory antibody-drug conjugate targeting BDCA2 strongly suppresses plasmacytoid dendritic cell function and glucocorticoid responsive genes.

OBJECTIVES: Blood dendritic cell antigen 2 (BDCA2) is exclusively expressed on plasmacytoid dendritic cells (pDCs) whose uncontrolled production of type I IFN (IFN-I) is crucial in pathogenesis of SLE and other autoimmune diseases. Although anti-BDCA2 antibody therapy reduced disease activity in SLE patients, its clinical efficacy needs further improvement. We developed a novel glucocorticoid receptor agonist and used it as a payload to conjugate with an anti-BDCA2 antibody to form an BDCA2 antibody-drug conjugate (BDCA2-ADC). The activation of BDCA2-ADC was evaluated in vitro. METHODS: Inhibitory activity of BDCA2-ADC was evaluated in peripheral blood mononuclear cells or in purified pDCs under ex vivo toll-like receptor agonistic stimulation. The global gene regulation in purified pDCs was analysed by RNA-seq. The antigen-dependent payload delivery was measured by reporter assay. RESULTS: The BDCA2-ADC molecule causes total suppression of IFNα production and broader inhibition of inflammatory cytokine production compared with the parental antibody in human pDCs. Global gene expression analysis confirmed that the payload and antibody acted synergistically to regulate both type I IFN signature genes and glucocorticoid responsive genes in pDCs. CONCLUSION: Taken together, these data suggest dual mechanisms of BDCA2-ADC on pDCs and the potential for BDCA2-ADC to be the first ADC treatment for SLE in the world and a better treatment option than anti-BDCA2 antibody for SLE patients.

The contrast-free diffusion MRI multiple index for the early prediction of pathological response to neoadjuvant chemotherapy in breast cancer.

Early tumor response prediction can help avoid overtreatment with unnecessary chemotherapy sessions. It is important to determine whether multiple apparent diffusion coefficient indices (S index, ADC-diff) are effective in the early prediction of pathological response to neoadjuvant chemotherapy (NAC) in breast cancer (BC). Patients with stage II and III BCs who underwent T1WI, diffusion-weighted imaging (DWI), and dynamic contrast-enhanced MRI using a 3 T system were included. They were divided into two groups: major histological responders (MHRs, Miller-Payne G4/5) and nonmajor histological responders (nMHRs, Miller-Payne G1-3). Three b values were used for DWI to derive the S index; ADC-diff values were obtained using b = 0 and 1000 s/mm2. The different interquartile ranges of percentile S-index and ADC-diff values after treatment were calculated and compared. The assessment was performed at baseline and after two and four NAC cycles. A total of 59 patients were evaluated. There are some correlations of interquartile ranges of S-index parameters and ADC-diff values with histopathological prognostic factors (such as estrogen receptor and human epidermal growth factor receptor 2 expression, all p < 0.05), but no significant differences were found in some other interquartile ranges of S-index parameters or ADC-diff values between progesterone receptor positive and negative or for Ki-67 tumors (all P > 0.05). No differences were found in the dynamic contrast-enhanced MRI characteristics between the two groups. HER-2 expression and kurtosis of the S-index distribution were screened out as independent risk factors for predicting MHR group (p < 0.05, area under the curve (AUC) = 0.811) before NAC. After early NAC (two cycles), only the 10th percentile S index was statistically significant between the two groups (p < 0.05, AUC = 0.714). No significant differences were found in ADC-diff value at any time point of NAC between the two groups (P > 0.1). These findings demonstrate that the S-index value may be used as an early predictor of pathological response to NAC in BC; the value of ADC-diff as an imaging biomarker of NAC needs to be further confirmed by ongoing multicenter prospective trials.

Therapeutic antibodies for the prevention and treatment of cancer.

The developments of antibodies for cancer therapeutics have made remarkable success in recent years. There are multiple factors contributing to the success of the biological molecule including origin of the antibody, isotype, affinity, avidity and mechanism of action. With better understanding of mechanism of cancer progression and immune manipulation, recombinant formats of antibodies are used to develop therapeutic modalities for manipulating the immune cells of patients by targeting specific molecules to control the disease. These molecules have been successful in minimizing the side effects instead caused by small molecules or systemic chemotherapy but because of the developing therapeutic resistance against these antibodies, combination therapy is thought to be the best bet for patient care. Here, in this review, we have discussed different aspects of antibodies in cancer therapy affecting their efficacy and mechanism of resistance with some relevant examples of the most studied molecules approved by the US FDA.

Calendar-period trends in cervical precancer and cancer diagnoses since the introduction of human papillomavirus and cytology co-testing into routine cervical cancer screening at Kaiser Permanente Northern California.

OBJECTIVES: The longer-term impact of introducing human papillomavirus (HPV) testing into routine cervical cancer screening on precancer and cancer rates by histologic type has not been well described. Calendar trends in diagnoses were examined using data from Kaiser Permanente Northern California, which introduced triennial HPV and cytology co-testing in 2003 for women aged ≥30 years. METHODS: We examined trends in cervical precancer (cervical intraepithelial neoplasia grade 3 [CIN3] and adenocarcinoma in situ [AIS]) and cancer (squamous cell carcinoma [SCC] and adenocarcinoma [ADC]) diagnoses per 1000 screened during 2003-2018. We examined ratios of squamous vs. glandular diagnoses (SCC:ADC and CIN3:AIS). RESULTS: CIN3 and AIS diagnoses increased approximately 2% and 3% annually, respectively (ptrend < 0.001 for both). While SCC diagnoses decreased by 5% per annually (ptrend < 0.001), ADC diagnoses did not change. These patterns were generally observed within each age group (30-39, 40-49, and 50-64 years). ADC diagnoses per 1000 screened did not change even among those who underwent co-testing starting in 2003-2006. SCC:ADC decreased from approximately 2.5:1 in 2003-2006 to 1.3:1 in 2015-2018 while the CIN3:AIS remained relatively constant, ∼10:1. CONCLUSIONS: Since its introduction at KPNC, co-testing increased the detection of CIN3 over time, which likely caused a subsequent reduction of SCC. However, there has been no observed decrease in ADC. One possible explanation for lack of effectiveness against ADC is the underdiagnosis of AIS. Novel strategies to identify and treat women at high risk of ADC need to be developed and clinically validated.

Association of peritumoral region features assessed on breast MRI and prognosis of breast cancer: a systematic review and meta-analysis.

BACKGROUND: Increasing attention has been given to the peritumoral region. However, conflicting findings have been reported regarding the relationship between peritumoral region features on MRI and the prognosis of breast cancer. PURPOSE: To evaluate the relationship between peritumoral region features on MRI and prognosis of breast cancer. MATERIALS AND METHODS: A retrospective meta-analysis of observational studies comparing either qualitative or quantitative assessments of peritumoral MRI features on breast cancer with poor prognosis and control subjects was performed for studies published till October 2022. Pooled odds ratios (ORs) or standardized mean differences and 95% confidence intervals (CIs) were estimated by using random-effects models. The heterogeneity across the studies was measured using the statistic I2. Sensitivity analyses were conducted to test this association according to different study characteristics. RESULTS: Twenty-four studies comprising 1853 breast cancers of poor prognosis and 2590 control participants were included in the analysis. Peritumoral edema was associated with non-luminal breast cancers (OR=3.56; 95%CI: 2.17, 5.83; p=.000), high expression of the Ki-67 index (OR=3.70; 95%CI: 2.41, 5.70; p =.000), high histological grade (OR=5.85; 95%CI: 3.89, 8.80; p=.000), lymph node metastasis (OR=2.83; 95%CI: 1.71, 4.67; p=.000), negative expression of HR (OR=3.15; 95%CI: 2.03, 4.88; p=.000), and lymphovascular invasion (OR=1.72; 95%CI: 1.28, 2.30; p=.000). The adjacent vessel sign was associated with greater odds of breast cancer with poor prognosis (OR=2.02; 95%CI: 1.68, 2.44; p=.000). Additionally, breast cancers with poor prognosis had higher peritumor-tumor ADC ratio (SMD=0.67; 95%CI: 0.54, 0.79; p=.000) and peritumoral ADCmean (SMD=0.29; 95%CI: 0.15, 0.42; p=.000). A peritumoral region of 2-20 mm away from the margin of the tumor is recommended. CONCLUSION: The presence of peritumoral edema and adjacent vessel signs, higher peritumor-tumor ADC ratio, and peritumoral ADCmean were significantly correlated with poor prognosis of breast cancer. CLINICAL RELEVANCE STATEMENT: MRI features of the peritumoral region can be used as a non-invasive index for the prognostic evaluation of invasive breast cancer. KEY POINTS: • Peritumoral edema was positively associated with non-luminal breast cancer, high expression of the Ki-67 index, high histological grade, lymph node metastasis, negative expression of HR, and lymphovascular invasion. • The adjacent vessel sign was associated with greater odds of breast cancers with poor prognosis. • Breast cancers with poor prognosis had higher peritumor-tumor ADC ratio and peritumoral ADCmean.

Merocyanines form bacteriorhodopsins with strongly bathochromic absorption maxima.

There is a need to shift the absorbance of biomolecules to the optical transparency window of tissue for applications in optogenetics and photo-pharmacology. There are a few strategies to achieve the so-called red shift of the absorption maxima. Herein, a series of 11 merocyanine dyes were synthesized and employed as chromophores in place of retinal in bacteriorhodopsin (bR) to achieve a bathochromic shift of the absorption maxima relative to bR's [Formula: see text] of 568 nm. Assembly with the apoprotein bacterioopsin (bO) led to stable, covalently bound chromoproteins with strongly bathochromic absorbance bands, except for three compounds. Maximal red shifts were observed for molecules 9, 2, and 8 in bR where the [Formula: see text] was 766, 755, and 736 nm, respectively. While these three merocyanines have different end groups, they share a similar structural feature, namely, a methyl group which is located at the retinal equivalent position 13 of the polyene chain. The absorption and fluorescence data are also presented for the retinal derivatives in their aldehyde, Schiff base (SB), and protonated SB (PSB) forms in solution. According to their hemicyanine character, the PSBs and their analogue bRs exhibited fluorescence quantum yields (Φf) several orders of magnitude greater than native bR (Φf 0.02 to 0.18 versus 1.5 × 10-5 in bR) while also exhibiting much smaller Stokes shifts than bR (400 to 1000 cm-1 versus 4030 cm-1 in bR). The experimental results are complemented by quantum chemical calculations where excellent agreement between the experimental [Formula: see text] and the calculated [Formula: see text] was achieved with the second-order algebraic-diagrammatic construction [ADC(2)] method. In addition, quantum mechanics/molecular mechanics (QM/MM) calculations were employed to shed light on the origin of the bathochromic shift of merocyanine 2 in bR compared with native bR.

ADC Values for Detecting Bowel Inflammation and Biologic Therapy Response in Patients With Crohn Disease: A Post Hoc Prospective Trial Analysis.

BACKGROUND. New biologic agents for Crohn disease (CD) create a need for noninvasive disease markers. DWI may assess bowel inflammation without contrast agents. OBJECTIVE. The purpose of this study was to evaluate ADC values for identifying bowel inflammation and therapeutic response in patients with CD treated with biologic therapy. METHODS. This study entailed post hoc analysis of prospective trial data. Analysis included 89 patients (median age, 37 years; 49 women, 40 men) with CD treated by biologic therapy who underwent MR enterography (MRE) at baseline and 46 weeks after therapy, from March 2013 to April 2021; 43 patients underwent ileocolonoscopy at both time points. Analysis was conducted at the level of small-bowel and colorectal segments (586 segments analyzed). MR index of activity (MaRIA) score and presence of endoscopic ulcers were determined at both time points. One observer measured bowel wall ADC. Diagnostic performance was evaluated. Dichotomous ADC assessments used a threshold of 1301 × 10-6 mm2/s based on initial ROC analysis; dichotomous MaRIA score assessments used a threshold of 11 (moderate to severe inflammation). A second observer repeated ADC measurements in 15 patients. RESULTS. At baseline, ADC had AUC of 0.92, sensitivity of 78.6%, specificity of 91.4%, and accuracy of 88.2% for detecting segments with MaRIA score 11 or greater. At baseline, AUC for detecting endoscopic ulcers was 0.96 for MaRIA score versus 0.87 for ADC (p < .001); sensitivity, specificity, and accuracy were 70.8%, 90.2%, and 85.1% for ADC and 86.2%, 96.2%, and 93.6% for MaRIA score. At follow-up, ADC had AUC of 0.87, sensitivity of 75.4%, specificity of 83.6%, and accuracy of 80.0% for detecting improvement in MaRIA score to less than 11. At follow-up, AUC for detecting endoscopic ulcer healing was 0.94 for MaRIA score versus 0.84 for ADC (p = .01); sensitivity, specificity, and accuracy were 70.7%, 95.8%, and 84.4% for ADC and 90.2%, 100.0%, and 95.6% for MaRIA score. Interobserver agreement for ADC, based on intraclass correlation coefficient, was 0.70 at baseline and 0.65 at follow-up. CONCLUSION. The findings do not support use of ADC rather than MaRIA scores for detecting biologic therapy response. CLINICAL IMPACT. ADC may have an adjunct role in assessing bowel inflammation in CD, but showed limited performance for detecting biologic therapy response.

Utility of ADC Values for Differentiating Uterine Sarcomas From Leiomyomas: Systematic Review and Meta-Analysis.

Background: Uterine sarcomas are rare; however, they display imaging features that overlap those of leiomyomas. The potential for undetected uterine sarcomas is clinically relevant because minimally invasive treatment of leiomyomas may lead to cancer dissemination. ADC values have shown potential for differentiating benign and malignant uterine masses. Objective: The purpose of this study was to perform a systematic review of the diagnostic performance of ADC values in differentiating uterine sarcomas from leiomyomas. Evidence acquisition: We searched three electronic databases (MEDLINE, EMBASE, and Cochrane databases) for studies distinguishing uterine sarcomas from leiomyomas using MRI, including ADC, with pathologic tissue confirmation or imaging follow-up as the reference standard. Data extraction and QUADAS-2 quality assessment were performed. Sensitivity and specificity were pooled using hierarchic models, including bivariate and hierarchic summary ROC models. Metaregression was used to assess the impact of various factors on heterogeneity. Evidence synthesis: Twenty-one studies met study inclusion criteria. Pooled sensitivity and specificity were 89% (95% CI, 82-94%) and 86% (95% CI, 78-92%), respectively. Area under the summary ROC curve was 94% (95% CI, 92-96%). Context of ADC interpretation (i.e., standalone vs part of multiparametric MRI [mpMRI]) was the only factor found to account significantly for heterogeneity (p = .01). Higher specificity (95% [95% CI, 92-99%] vs 82% [95% CI, 75-89%]) and similar sensitivity (94% [95% CI, 89-99%] vs 88% [95% CI, 82-93%]) were observed when ADC was evaluated among mpMRI features as compared with standalone ADC assessment. ADC cutoff values ranged (0.87-1.29 × 10-3 mm2/s) but were not associated with statistically different performance (p = .37). Pooled mean ADC values in sarcomas and leiomyomas were 0.904 × 10-3 mm2/s and 1.287 × 10-3 mm2/s, respectively. Conclusion: As part of mpMRI evaluation of uterine masses, mass ADC value less than 0.904 × 10-3 mm2/s may be a useful test-positive threshold for uterine sarcoma, consistent with a prior expert consensus statement. Institutional protocols may influence locally selected ADC values. Clinical Impact: Using ADC as part of mpMRI assessment improves detection of uterine sarcoma, which could influence candidate selection for minimally invasive treatments.

Design and synthesis of novel site-specific antibody-drug conjugates that target TROP2.

The approval of Trodelvy® validates TROP2 as a druggable but challenging target for antibody-drug conjugates (ADCs) to treat metastatic triple-negative breast cancer (mTNBC). Here, based on the TROP2-targeted antibody sacituzumab, we designed and developed several site-specific ADC candidates, which employ MMAE (monomethyl auristatin E) as the toxin, via IgG glycoengineering or affinity-directed traceless conjugation. Systematic evaluation of these site-specific ADCs in homogeneity, hydrophilicity, stability, and antitumor efficiency was conducted. The results indicate that the site-specific ADCs gsADC 3b made from one-step glycoengineering exhibit good aggregation stability and in vivo efficacy, providing a new format of ADCs that target TROP2.

Pioneering the Way: The Revolutionary Potential of Antibody-Drug Conjugates in NSCLC.

OPINION STATEMENT: Despite targeted therapy and immunotherapy being recognized as established frontline treatments for advanced non-small cell lung cancer (NSCLC), the unavoidable development of resistance and disease progression poses ongoing challenges. Antibody-drug conjugates (ADCs) offer a potent treatment option for NSCLC through the specific delivery of cytotoxic agents to tumor cells that display distinct antigens. This review delves into the latest evidence regarding promising ADC agents for NSCLC, focusing on their targets, effectiveness, and safety assessments. Additionally, our study provides insights into managing toxicities, identifying biomarkers, devising methods to counter resistance mechanisms, tackling prevailing challenges, and outlining prospects for the clinical implementation of these innovative ADCs and combination regimens in NSCLC.

TROPION-Breast01: Datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2- breast cancer.

Improving the prognosis for patients with metastatic HR+/HER2- breast cancer remains an unmet need. Patients with tumors that have progressed on endocrine therapy and/or are not eligible for endocrine therapy had limited treatment options beyond chemotherapy. Antibody-drug conjugates are a novel and promising treatment class in this setting. Datopotamab deruxtecan (Dato-DXd) consists of a TROP2-directed humanized IgG1 monoclonal antibody attached via a serum-stable cleavable linker to a topoisomerase I inhibitor payload. TROPION-Breast01 is an ongoing phase III study that is evaluating the efficacy and safety of Dato-DXd compared with investigator's choice of standard-of-care chemotherapy in patients with inoperable or metastatic HR+/HER2- breast cancer who have received one or two prior lines of systemic chemotherapy in the inoperable or metastatic setting. Clinical Trial Registration: NCT05104866 (ClinicalTrials.gov).

Antibody-drug conjugates are a type of drug with two parts: an antibody that directs the drug to the cancer cells and a cancer-cell killing toxic payload. By binding to cancer cells before releasing the payload, treatment is directed to the site of action so there are fewer side effects in the rest of the body. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugates made up of datopotamab (antibody) and DXd (payload) which are joined together via a stable linker. Datopotamab binds to a protein found on cancer cells called TROP2; it then goes inside and releases the DXd payload to kill the tumor cells. DXd may leak out to surrounding cancer cells and kill those as well. The TROPION-Breast01 study is comparing Dato-DXd with standard-of-care chemotherapy. Around 700 patients will take part, who have: Tumors that cannot be surgically removed. Tumors that are hormone receptor-positive and do not have HER2 overexpression. Had one or two lines of previous chemotherapy (after the tumor could not be surgically removed, or had spread). Had tumor growth despite hormonal therapy or are ineligible for hormonal therapy. Patients who meet the entry criteria will be randomly assigned to a treatment group in equal numbers to either Dato-DXd or an appropriate chemotherapy, out of four options chosen by the treating doctor. At the end of the study, researchers will look at whether the patients who receive Dato-DXd live longer without their breast cancer getting worse, compared with patients who receive chemotherapy. This study is also looking at how the treatment affects patients' quality of life.