MYTX-011: A pH-Dependent Anti-c-MET Antibody-Drug Conjugate Designed for Enhanced Payload Delivery to c-MET-Expressing Tumor Cells.

Advances in linker payload technology and target selection have been at the forefront of recent improvements in antibody-drug conjugate (ADC) design, leading to several approvals over the last decade. In contrast, the potential of novel ADC technologies to enhance payload delivery to tumors is relatively underexplored. We demonstrate that incorporation of pH-dependent binding in the antibody component of a c-mesenchymal-epithelial transition (MET)-targeting ADC (MYTX-011) can overcome the requirement for high c-MET expression on tumors, an innovation that has the potential to benefit a broader population of patients with lower c-MET levels. MYTX-011 drove fourfold higher net internalization than a non-pH-engineered parent ADC in non-small cell lung cancer (NSCLC) cells and showed increased cytotoxicity against a panel of cell lines from various solid tumors. A single dose of MYTX-011 showed at least threefold higher efficacy than a benchmark ADC in mouse xenograft models of NSCLC ranging from low to high c-MET expression. Moreover, MYTX-011 showed improved pharmacokinetics over parent and benchmark ADCs. In a repeat dose toxicology study, MYTX-011 exhibited a toxicity profile similar to other monomethyl auristatin E-based ADCs. These results highlight the potential of MYTX-011 for treating a broader range of patients with NSCLC with c-MET expression than other c-MET-targeting ADCs. A first-in-human study is ongoing to determine the safety, tolerability, and preliminary efficacy of MYTX-011 in patients with NSCLC (NCT05652868).

MYTX-011: a pH-dependent anti-cMET antibody-drug conjugate designed for enhanced payload delivery to cMET expressing tumor cells.

Advances in linker payload technology and target selection have been at the forefront of recent improvements in antibody-drug conjugate (ADC) design, leading to several approvals over the last decade. In contrast, the potential of novel ADC technologies to enhance payload delivery to tumors is relatively underexplored. We demonstrate that incorporation of pH-dependent binding in the antibody component of a cMET targeting ADC (MYTX-011) can overcome the requirement for high cMET expression on tumors, an innovation that has the potential to benefit a broader population of patients with lower cMET levels. MYTX-011 drove four-fold higher net internalization than a non-pH engineered parent ADC in non-small cell lung cancer (NSCLC) cells and showed increased cytotoxicity against a panel of cell lines from various solid tumors. A single dose of MYTX-011 showed at least three-fold higher efficacy than a benchmark ADC in mouse xenograft models of NSCLC ranging from low to high cMET expression. Moreover, MYTX-011 showed improved pharmacokinetics over parent and benchmark ADCs. In a repeat dose toxicology study, MYTX-011 exhibited a toxicity profile similar to other MMAE-based ADCs. These results highlight the potential of MYTX-011 for treating a broader range of NSCLC patients with cMET expression than other cMET targeting ADCs. A first in human study is ongoing to determine the safety, tolerability, and preliminary efficacy of MYTX-011 in patients with NSCLC (NCT05652868).

TTLL12 has a potential oncogenic activity, suppression of ligation of nitrotyrosine to the C-terminus of detyrosinated α-tubulin, that can be overcome by molecules identified by screening a compound library.

Tubulin tyrosine ligase 12 (TTLL12) is a promising target for therapeutic intervention since it has been implicated in tumour progression, the innate immune response to viral infection, ciliogenesis and abnormal cell division. It is the most mysterious of a fourteen-member TTL/TTLL family, since, although it is the topmost conserved in evolution, it does not have predicted enzymatic activities. TTLL12 seems to act as a pseudo-enzyme that modulates various processes indirectly. Given the need to target its functions, we initially set out to identify a property of TTLL12 that could be used to develop a reliable high-throughput screening assay. We discovered that TTLL12 suppresses the cell toxicity of nitrotyrosine (3-nitrotyrosine) and its ligation to the C-terminus of detyrosinated α-tubulin (abbreviated to ligated-nitrotyrosine). Nitrotyrosine is produced by oxidative stress and is associated with cancer progression. Ligation of nitrotyrosine has been postulated to be a check-point induced by excessive cell stress. We found that the cytotoxicities of nitrotyrosine and tubulin poisons are independent of one another, suggesting that drugs that increase nitrotyrosination could be complementary to current tubulin-directed therapeutics. TTLL12 suppression of nitrotyrosination of α-tubulin was used to develop a robust cell-based ELISA assay that detects increased nitrotyrosination in cells that overexpress TTLL12 We adapted it to a high throughput format and used it to screen a 10,000 molecule World Biological Diversity SETTM collection of low-molecular weight molecules. Two molecules were identified that robustly activate nitrotyrosine ligation at 1 µM concentration. This is the pioneer screen for molecules that modulate nitrotyrosination of α-tubulin. The molecules from the screen will be useful for the study of TTLL12, as well as leads for the development of drugs to treat cancer and other pathologies that involve nitrotyrosination.

M9657 Is a Bispecific Tumor-Targeted Anti-CD137 Agonist That Induces MSLN-Dependent Antitumor Immunity without Liver Inflammation.

The costimulatory receptor CD137 (also known as TNFRSF9 or 4-1BB) sustains effective cytotoxic T-cell responses. Agonistic anti-CD137 cancer immunotherapies are being investigated in clinical trials. Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated by Fcγ receptors (FcγR) ligand-dependent CD137 activation, respectively. M9657 was engineered as a tetravalent bispecific antibody (mAb2) in a human IgG1 backbone with LALA mutations to reduce binding to FCγRs. Here, we report that M9657 selectively binds to mesothelin (MSLN) and CD137 with similar affinity in humans and cynomolgus monkeys. In a cellular functional assay, M9657 enhanced CD8+ T cell-mediated cytotoxicity and cytokine release in the presence of tumor cells, which was dependent on both MSLN expression and T-cell receptor/CD3 activation. Both FS122m, a murine surrogate with the same protein structure as M9657, and chimeric M9657, a modified M9657 antibody with the Fab portion replaced with an anti-murine MSLN motif, demonstrated in vivo antitumor efficacy against various tumors in wild-type and human CD137 knock-in mice, and this was accompanied by activated CD8+ T-cell infiltration in the tumor microenvironment. The antitumor immunity of M9657 and FS122m depended on MSLN expression density and the mAb2 structure. Compared with 3H3, a murine surrogate of urelumab, FS122m and chimeric M9657 displayed significantly lower on-target/off-tumor toxicity. Taken together, M9657 exhibits a promising profile for development as a tumor-targeting immune agonist with potent anticancer activity without systemic immune activation and associated hepatotoxicity.

Catheters in vascular interventional radiology: an illustrated review.

The past five decades have seen significant developments in the knowledge and practice of interventional radiology. Advancements in angiographic equipment have made interventional radiology a safe, minimally invasive preferred option in the treatment of a variety of diseases. Today, a range of catheters are available in the armamentarium of the interventional radiologist to suit different needs when conducting diagnostic angiograms or performing interventions in various vascular territories. The hardware required for interventions includes needles, wires, catheters, balloons, and stents. Catheters, in particular, are an invaluable tool for interventionists. The purpose of this review is to describe the identification characteristics, properties, and uses of the common angiographic catheters used in interventional radiology, with a special focus on peripheral vascular interventions (excluding neurointerventions).

Stent-Graft Migration Post-Endovascular Repair of Thoracic Aorta: A Retrospective Cohort Study.

Background Migration of the stent-graft post-thoracic endovascular aortic repair (TEVAR) is not uncommon; however, it is sparsely reported. The objective of this study was to assess the incidence, risk factors, and complications of stent-graft migration post-TEVAR. Materials and Methods Thirty-one patients who underwent TEVAR were retrospectively analyzed. The demographic, anatomical, and procedure-related factors were assessed. The measurements were done along the greater curvature of aorta around two fixed anatomic landmarks, that is, left common carotid artery or neoinnominate artery (hybrid repair) proximally and celiac artery distally. Aortic elongation and migration at proximal, distal, as well as at overlapping zone were measured. More than 10 mm of migration was considered significant. Results Significant migration was observed in six (19%) patients. No significant migration was observed in the overlapping zone. The proximal landing zone 3 (odds ratio [OR] 12.78, p 0.01) was a significant risk factor, whereas landing zone 2 was a protective factor against the migration (OR 0.08, p 0.02). The odds for migration were more in segments I/3 and II/3 compared with I/2 and II/2, respectively, as per Modified Arch Landing Areas Nomenclature. A single complication was seen in the migration group which was treated by an overlapping stent graft. Conclusion The stent-graft migration after TEVAR is not uncommon. Type 3 proximal landing zone was a significant risk factor for migration with an increased risk toward I/3 and II/3. Proximal landing zone 2 as well as adequate overlapping distance in multiple stent grafts can prevent migration. Ethical Approval No IECPG-227/24.06.2020.

Association between aortic coverage and spinal cord ischemia after endovascular repair of type B aortic dissection.

Objectives: To examine the association between aortic coverage and occurrence of spinal cord ischemia (SCI) after thoracic endovascular aortic repair (TEVAR) for type B aortic dissection. Methods: Thirty-eight consecutive patients (mean age 52 years; 35 men) who underwent TEVAR for type B aortic dissection at our centre were included. Patients were stratified into two groups based on stent graft length (SGL): group I (≤ 200 mm; n = 19) and group II (> 200 mm; n = 19). All the procedures were performed under strict blood pressure monitoring. Preoperative cerebrospinal fluid (CSF) drain was instituted in two patients. Results: Mean SGLs were 200 mm in group I and 277 ± 27 mm in group II. The number of segmental arteries covered was significantly different between the two groups (p < 0.001). There was no significant difference in vertebral artery dominance between groups I and II (p = 0.99). One patient in group II, who also had bilateral internal iliac artery occlusion, developed postprocedural neurological deficit referrable to SCI, which resolved completely after institution of CSF drainage. However, the incidence of SCI was not significantly different between group I and group II (p = 0.5). Conclusion: Based on our experience, we recommend longer aortic coverage (beyond 200 mm) in type B aortic dissection (TBAD) for better aortic remodelling, provided that the mean arterial pressure of > 90 mm Hg is maintained perioperatively to avoid SCI.

Evaluation of Remodeling of Visceral Arteries and Impact on Renal Function Post-endovascular Repair of Type B Aortic Dissection Vis-A-Vis Baseline Visceral Artery Morphology.

PURPOSE: To evaluate the remodeling of visceral arteries post-endovascular repair (TEVAR) of type B aortic dissection and to investigate interval change in renal volume and estimated glomerular filtration rate (eGFR) vis-a-vis baseline visceral artery morphology. MATERIALS AND METHODS: All patients of type B aortic dissection who underwent TEVAR with a baseline and follow-up CT during the study period were included. Baseline morphology of visceral arteries (celiac, superior, and inferior mesenteric artery and bilateral renal artery) were classified into 7 patterns depending upon the origin of the artery (from true/false lumen) and the extension of dissection flap, while occluded vessels were categorized as pattern 8. RESULTS: One hundred and thirty-two branches were analyzed in 25 patients (23 males; mean age: 50.1 years) with a mean follow-up of 386 days. 51 visceral branches were arising from the true lumen without any stenosis. Of the remaining 81 branches, 48 showed favorable remodeling (P = .0001). The highest incidence of favorable remodeling was observed in arteries arising from the true lumen (pattern 2,3: 44/48; 91.6%) whereas only one thrombosed and artery arising from the false lumen each (pattern 5 and 8) showed favorable remodeling. Kidneys perfused by false lumen or occluded renal artery suffered statistically significant volume loss compared to kidneys perfused by true or both lumens (-16.5% vs .2%; P = .01); however, the change in eGFR failed to reach statistical significance. CONCLUSION: Visceral arteries arising from the true lumen are more likely to undergo favorable remodeling. The kidneys supplied by false lumen or by occluded renal artery suffer significantly more volume loss after TEVAR.

Female pseudohermaphroditism with urethral duplication: A delayed presentation in adulthood.

Female pseudohermaphroditism with urethral duplication presenting as urinary retention in adulthood is extremely rare. We report the case of a 26-year-old female who had multiple failed attempts of per urethral catheterization during a planned cesarean section. She had labial fusion and clitoral hypertrophy with a phallic urethra and underwent labial separation with urethral reconstruction.

Periaortic air in native and post-operative aorta on computed tomography.

Periaortic air can be seen in various conditions which can be a benign imaging finding or harbinger of a catastrophic event. The causes vary in native aorta and post-operative aorta. A radiologist has an important part in the management process of these patients, as the treatment varies from conservative to radical surgery based on the aetiology. The presence of periaortic air seen in the light of various clinical, laboratory and radiological findings can guide the radiologist towards a particular aetiology. Cross-sectional imaging, mainly computed tomography, is an indispensable tool in recognising ectopic periaortic air and to identify the associated findings and eventually make an accurate diagnosis. We present a pictorial review of various causes of the periaortic air in native and postoperative aorta, the salient features and management of the described conditions.

Unruptured sinus of valsalva aneurysm in a case of large vessel vasculitis: A diagnostic dilemma.

BACKGROUND: Takayasu arteritis and tuberculous aortitis, both can result in aneurysmal disease of the aorta. The overlapping imaging features in case of large vessel vasculitis can create a diagnostic dilemma. AIM: We present a case of large vessel vasculitis and chronic empyema with unruptured sinus of valsalva aneurysm. METHODS AND RESULTS: A 30-year-old man presented with acute onset shortness of breath, palpitations, and gradually progressing pedal edema. The echocardiography and CT angiogram revealed features of large vessel vasculitis and chronic empyema along with unruptured sinus of valsava aneurysms. Patient underwent emergency Bentall procedure and the histopathology confirmed the diagnosis of takayasu arteritis. DISCUSSION: Tuberculosis being an endemic disease with varied presentations should always be considered a differential diagnosis, whenever appropriate. An unruptured sinus of valsalva aneurysm can be clinically silent or can cause compression symptoms. Although there are no specific guidelines regarding surgical correction, symptomatic and aneurysms of size >5.5cm are usually managed surgically. CONCLUSION: Unruptured sinus of valsalva aneurysms can be seen in Takayasu arteritis, which complicates the methodology and timing of the surgical management.

Delayed presentation of an organized chronic intrapericardial hematoma with diastolic dysfunction.

We describe the case of a 45-year-old man, with a history of blunt trauma to the chest 2 years back, presenting with diastolic dysfunction secondary to the development of a large, organized, intrapericardial hematoma. The case highlights the possibility of extremely delayed presentation in such cases and the importance of cardiac magnetic resonance imaging in making an accurate preoperative diagnosis and guiding optimal management strategies.

A rare pediatric case of bilateral bronchopulmonary vascular malformations and right isomerism.

We present an unusual case of an 18-day-old term neonate with coexistent bilateral bronchopulmonary vascular malformations and right isomerism. This case highlights the importance of computed tomography angiography in depicting such complex anomalies and classifying them according to components involved providing a systematic approach for evaluation of the disease process.