Joseph Kalen - Academia.edu (original) (raw)

Papers by Joseph Kalen

Journal of the American Chemical Society, Dec 20, 2021

Antibody-drug conjugates (ADCs) are a rapidly emerging therapeutic platform. The chemical linker ... more Antibody-drug conjugates (ADCs) are a rapidly emerging therapeutic platform. The chemical linker between the antibody and the drug payload plays an essential role in the efficacy and tolerability of these agents. New methods that quantitively assess cleavage efficiency in complex tissue settings could provide valuable insights into the ADC design process. Here we report the development of a near-infrared (NIR) optical imaging approach that measures the site and extent of linker cleavage in mouse models. This approach is enabled by a superior variant of our recently devised cyanine carbamate (CyBam) platform. We identify a novel tertiary amine-containing norcyanine, the product of CyBam cleavage, that exhibits dramatically increased cellular signal due to improved cellular permeability and lysosomal accumulation. The resulting cyanine lysosome-targeting carbamates (CyLBams) are ~50X brighter in cells, and we find this strategy is essential for high-contrast in vivo targeted imaging. Finally, we compare a panel of several common ADC linkers across two antibodies and tumor models. These studies indicate that cathepsin-cleavable linkers provide dramatically higher tumor activation relative to hindered or non-hindered disulfides-an observation that is only apparent with in vivo imaging. This strategy enables quantitative comparisons of cleavable linker chemistries in complex tissue settings with implications across the drug delivery landscape.

Angewandte Chemie, May 31, 2023

Heptamethine cyanine dyes enable deep tissue fluorescence imaging in the near infrared (NIR) wind... more Heptamethine cyanine dyes enable deep tissue fluorescence imaging in the near infrared (NIR) window. Small molecule conjugates of the benchmark dye ZW800‐1 have been tested in humans. However, long‐term imaging protocols using ZW800‐1 conjugates are limited by their instability, primarily because the chemically labile C4′‐O‐aryl linker is susceptible to cleavage by biological nucleophiles. Here, we report a modular synthetic method that produces novel doubly strapped zwitterionic heptamethine cyanine dyes, including a structural analogue of ZW800‐1, with greatly enhanced dye stability. NIR‐I and NIR‐II versions of these doubly strapped dyes can be conjugated to proteins, including monoclonal antibodies, without causing undesired fluorophore degradation or dye stacking on the protein surface. The fluorescent antibody conjugates show excellent tumor‐targeting specificity in a xenograft mouse tumor model. The enhanced stability provided by doubly strapped molecular design will enable new classes of in vivo NIR fluorescence imaging experiments with possible translation to humans.

Clinical Nuclear Medicine, Oct 1, 1994

Physical review, Feb 1, 1988

Proton capture reactions on targets of "B, ' C, ' N, ' 0, and Al were measured from Ep =20 to 100... more Proton capture reactions on targets of "B, ' C, ' N, ' 0, and Al were measured from Ep =20 to 100 MeV. The energy dependence of the 8~=60' differential cross sections are presented for captures populating the ground states of "C, "N, ' 0, "F, and "Si. Differential-cross-section and analyzing-power angular distributions are presented at bombarding energies of E"=20.8, 28.35, 49.2, and 49.69 MeV. Calculations from two capture-reaction models are compared to the data.

Journal of the American Ceramic Society, 1991

Oxygen diffusion in vitreous silica glass is studied using the gas exchange technique. The tracer... more Oxygen diffusion in vitreous silica glass is studied using the gas exchange technique. The tracer concentration profiles are consistent with a model based on two mechanisms, one network and the other interstitial. These processes are coupled through limited network-interstitial exchange. Nuclear reaction analysis and secondary ion mass spectrometry techniques are performed and compared. These results are compared to experiments on transport in thin silica films grown on single-crystal silicon.

Recently there has been a revival of theoretical interest in modeling radiative capture reactions... more Recently there has been a revival of theoretical interest in modeling radiative capture reactions in the energy range from 100 MeV to the region of the A resonance near 300 MeV.

Journal of the American Chemical Society, Jun 27, 2023

ABSTRACT Theories describing radiative proton capture reactions above a proton energy E_{rm p } =... more ABSTRACT Theories describing radiative proton capture reactions above a proton energy E_{rm p } = 100 MeV contain different contributions of meson exchange terms or a possible contribution of a virtual Delta (1232 MeV) isobar. Differences in these theories result in contrasting analyzing power measurements in the forward and back angles. Studies of comparisons of these theories for the radiative proton capture reactions in the energy region 100 MeV

Journal of Nuclear Medicine Technology, Dec 1, 1996

Multihead camera inspection usually examines only head alignment with parallel-hole collimators, ... more Multihead camera inspection usually examines only head alignment with parallel-hole collimators, therefore, fanbeam collimators are not analyzed. We demonstrate that acceptance testing should include evaluating fanbeam collimator alignment. Methods: Two sets of low-energy ultra-high resolution (LEUHR) fanbeam collimators, Sets A (misaligned) and B (aligned), were examined. SPECT acquisitions were acquired for the three point sources aligned in the Z and Y directions, offset in the X direction and a three-dimensional Hoffman brain phantom. Results: Cinematic display of the raw data revealed artifactual motion in the Y direction for collimator Set A (misaligned), a SPECT spatial resolution (FWHM) increase of 4 mm in the Y direction and 1 mm in the X direction for Set A compared to Set B. Reconstructed images from the threedimensional Hoffman brain phantom resulted in no clinical discernible differences. Conclusion: We recommend testing fanbeam collimators during acceptance testing, before patient data is assumed to be reliable.

Biosensors and Bioelectronics, Dec 1, 2022

Physical review, Apr 1, 1988

ABSTRACT Similarities between cross sections and analyzing powers are reported for proton capture... more ABSTRACT Similarities between cross sections and analyzing powers are reported for proton capture into 1${d}_{5/2}$ orbits populating the ground state of 17mathrmF^{17}\mathrm{F}17mathrmF and the 3mathrmensuremath−{3}^{\mathrm{\ensuremath{-}}}3mathrmensuremath− second-excited state in 16mathrmO^{16}\mathrm{O}16mathrmO; for captures into 2${s}_{1/2}$ orbits populating the ground state of 29mathrmP^{29}\mathrm{P}29mathrmP and the 2+{2}^{+}2+ first-excited state in 28mathrmSi^{28}\mathrm{Si}28mathrmSi; and for the 1${d}_{3/2}$ orbits populating the (3/2+{(3/2}^{+}(3/2+ first-excited state in 29mathrmP^{29}\mathrm{P}29mathrmP and the 4+{4}^{+}4+ second-excited state in 28mathrmSi^{28}\mathrm{Si}28mathrmSi. The results are in reasonable accordance with the predictions of a direct-semidirect picture for nuclear capture reactions.

Physical review, Feb 1, 1989

ABSTRACT The radiative proton capture reaction on 15N was measured over the energy region Ep=20-9... more ABSTRACT The radiative proton capture reaction on 15N was measured over the energy region Ep=20-90 MeV. Presented are experimental differential cross sections at thetagamma=60° for captures populating the ground and various excited states of 160. Differential cross sections and analyzing-power angular distributions are presented at a proton energy of Ep=49.69 MeV. Calculations from a phenomenological direct-semidirect and a more detailed relativistic model describe cross sections well, but are less satisfactory in describing analyzing powers. Results of the energy-dependence measurements show that there are giant resonances built on all the excited states investigated.

Physics Letters B, 1995

The cross section for the *Li (a, n) "B reaction, of importance to primordial nucleosynthesis in ... more The cross section for the *Li (a, n) "B reaction, of importance to primordial nucleosynthesis in the inhomogeneous models, has been measured using a 'Li radioactive beam. The center-of-mass energy range studied was 0.64-2.2 MeV. The cross section to all "B states is found to exceed that for 8Li(cy, n) "B (g.s.) by a factor of at least five over the entire energy region studied. Studies of primordial nucleosynthesis have indicated that the abundances of the isotopes of H, He, Li, Be, and B are good test cases of our understanding of the conditions which prevailed in the early universe. The standard model (SM) [ 1,2] is known to produce rather good agreement with primordial abundances of nuclides up to mass 7 u, and to predict very tiny abundances of heavier elements. The recently developed inhomogeneous models [ 3-51 (IMs) predict abundances similar to those of the SM up to 4He, but produce estimates well in excess of those of the SM for 7Li and heavier nuclides, for much of their relevant parameter spaces. Although one recent study [6] of the predictions of the IMs concluded that the observed primordial abundances restricted the IM parameter space to a region which resulted in predictions very similar to

The Journal of Nuclear Medicine, May 1, 2021

Journal of Translational Medicine, Dec 1, 2019

Background: Spontaneously metastatic xenograft models of cancer are infrequent and the few that e... more Background: Spontaneously metastatic xenograft models of cancer are infrequent and the few that exist are resource intensive. In xenografts, caliper measurements can be used to determine primary tumor burden and response to therapy but in metastatic disease models determination of the presence of metastatic disease, metastatic burden, and response to therapy are difficult, often requiring serial necropsy. In this study we characterized the development of visceral metastases in a patient derived xenograft model (PDXM) using in vivo imaging. Results: We identified and characterized the previously unreported development of spontaneous liver and bone metastasis in a known patient derived xenograft, bladder xenograft BL0293F, developed by Jackson Laboratories and the University of California at Davis and available from the National Cancer Institute Patient-Derived Models Repository [1]. Among FDG-PET/CT, contrast-enhanced MRI and non-contrast MRI, non-contrast T2w MRI was the most effective and efficient imaging technique. On non-contrast T2 weighted MRI, hepatic metastases were observed in over 70% of animals at 52 days post tumor implantation without resection of the xenograft and in 100% of animals at day 52 following resection of the xenograft. In a group of animals receiving one cycle of effective chemotherapy, no animals demonstrated metastasis by imaging, confirming the utility of this model for therapy evaluation. There was good agreement between pathologic grade and extent of involvement observed on MRI T2w imaging. Conclusion: PDX BL0293F is a reliable visceral organ (liver) metastatic model with high penetrance in both nonaggravated and post excisional situations, providing a reliable window for therapy intervention prior to required excision of the xenograft. The imaging characteristics of this model are highly favorable for non-clinical research studies of metastatic disease when used in conjunction with non-contrast T2 weighted MRI.

Renal cell carcinoma (RCC) associated with Xp11.2 translocation (TFE3-RCC) has been recently defi... more Renal cell carcinoma (RCC) associated with Xp11.2 translocation (TFE3-RCC) has been recently defined as a distinct subset of RCC classified by characteristic morphology and clinical presentation. The Xp11 translocations involve the TFE3 transcription factor and produce chimeric TFE3 proteins retaining the basic helix-loop-helix leucine zipper structure for dimerization and DNA binding suggesting that chimeric TFE3 proteins function as oncogenic transcription factors. Diagnostic biomarkers and effective forms of therapy for advanced cases of TFE3-RCC are as yet unavailable. To facilitate the development of molecular based diagnostic tools and targeted therapies for this aggressive kidney cancer, we generated a translocation RCC mouse model, in which the PRCC-TFE3 transgene is expressed specifically in kidneys leading to the development of RCC with characteristic histology. Expression of the receptor tyrosine kinase Ret was elevated in the kidneys of the TFE3-RCC mice, and treatment with RET inhibitor, vandetanib, significantly suppressed RCC growth. Moreover, we found that Gpnmb (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that GPNMB is the direct transcriptional target of TFE3 fusions. While GPNMB IHC staining was positive in 9/9 cases of TFE3-RCC, Cathepsin K, a conventional marker for TFE3-RCC, was positive in only 67% of cases. These data support RET as a potential target and GPNMB as a diagnostic marker for TFE3-RCC. The TFE3-RCC mouse provides a preclinical in vivo model for the development of new biomarkers and targeted therapeutics for patients affected with this aggressive form of RCC. Implications: Key findings from studies with this preclinical mouse model of TFE3-RCC underscore the potential for RET as a therapeutic target for treatment of patients with TFE3-RCC, and suggest that GPNMB may serve as diagnostic biomarker for TFE3 fusion RCC.