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Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast and gastric/gastric esophageal junction cancers and treatment resistance remains a problem. Here, we engineer an anti-HER2 IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique and enhanced functionalities compared to both trastuzumab and the combination of trastuzumab plus pertuzumab (tras + pert). Zanidatamab binds adjacent HER2 molecules in trans and initiates distinct HER2 reorganization, as shown by polarized cell surface HER2 caps and large HER2 clusters, not observed with trastuzumab or tras + pert. Moreover, zanidatamab, but not trastuzumab nor tras + pert, elicit potent complement-dependent cytotoxicity (CDC) against high HER2-expressing tumor cells in vitro. Zanidatamab also mediates HER2 internalization and downregulation, inhibition of both cell signaling and tumor growth, antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), and also shows superior in vivo antitumor activity compared to tras + pert in a HER2-expressing xenograft model. Collectively, we show that zanidatamab has multiple and distinct mechanisms of action derived from the structural effects of biparatopic HER2 engagement. The success of HER2-targeted cancer therapy is limited by treatment resistance. Here, the authors engineer an anti-HER2 biparatopic antibody with multiple mechanisms of action including induction of HER2 clustering to trigger complement dependent cytotoxicity, signal inhibition, antibody dependent cellular cytotoxicity and phagocytosis.

Inhibitory receptors have been proposed to modulate the in vivo cytotoxic response against tumor targets for both spontaneous and antibody-dependent pathways 1 . Using a variety of syngenic and xenograft models, we demonstrate here that the inhibitory FcγRIIB molecule is a potent regulator of antibody-dependent cell-mediated cytotoxicity in vivo , modulating the activity of FcγRIII on effector cells. Although many mechanisms have been proposed to account for the anti-tumor activities of therapeutic antibodies, including extended half-life, blockade of signaling pathways, activation of apoptosis and effector-cell-mediated cytotoxicity, we show here that engagement of Fcγ receptors on effector cells is a dominant component of the in vivo activity of antibodies against tumors. Mouse monoclonal antibodies, as well as the humanized, clinically effective therapeutic agents trastuzumab (Herceptin ® ) and rituximab (Rituxan ® ), engaged both activation (FcγRIII) and inhibitory (FcγRIIB) antibody receptors on myeloid cells, thus modulating their cytotoxic potential. Mice deficient in FcγRIIB showed much more antibody-dependent cell-mediated cytotoxicity; in contrast, mice deficient in activating Fc receptors as well as antibodies engineered to disrupt Fc binding to those receptors were unable to arrest tumor growth in vivo . These results demonstrate that Fc-receptor-dependent mechanisms contribute substantially to the action of cytotoxic antibodies against tumors and indicate that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory partner FcγRIIB.

Kinetic Inductance Detectors (KIDs) are superconductive low-temperature detectors useful for astrophysics and particle physics. We have developed arrays of lumped elements KIDs (LEKIDs) sensitive to microwave photons, optimized for the four horn-coupled focal planes of the OLIMPO balloon-borne telescope, working in the spectral bands centered at 150 GHz, 250 GHz, 350 GHz, and 460 GHz. This is aimed at measuring the spectrum of the Sunyaev-Zel'dovich effect for a number of galaxy clusters, and will validate LEKIDs technology in a space-like environment. Our detectors are optimized for an intermediate background level, due to the presence of residual atmosphere and room-temperature optical system and they operate at a temperature of 0.3 K. The LEKID planar superconducting circuits are designed to resonate between 100 and 600 MHz, and to match the impedance of the feeding waveguides; the measured quality factors of the resonators are in the 104 - 105 range, and they have been tuned to obtain the needed dynamic range. The readout electronics is composed of a cold part, which includes a low noise amplifier, a dc-block, coaxial cables, and power attenuators; and a room-temperature part, FPGA-based, including up and down-conversion microwave components (IQ modulator, IQ demodulator, amplifiers, bias tees, attenuators). In this contribution, we describe the optimization, fabrication, characterization and validation of the OLIMPO detector system.

OLIMPO is a balloon-borne experiment aiming at spectroscopic measurements of the Sunyaev-Zel'dovich effect in clusters of galaxies. The instrument operates from the stratosphere, so that it can cover a wide frequency range (from ∼ 130 to ∼ 520 GHz in 4 bands), including frequencies which are not observable with ground-based instruments. OLIMPO is composed of a 2.6-m aperture telescope, a differential Fourier transform spectrometer and four arrays of lumped element kinetic inductance detectors operating at the temperature of 0.3 K. The payload was launched from the Longyearbyen airport (Svalbard Islands) on July 14th, 2018, and operated for 5 days, at an altitude of 38 km around the North Pole. We report the in-flight performance of the first lumped element kinetic inductance detector arrays ever flown onboard a stratospheric balloon.

We describe the in-flight performance of the horn-coupled lumped element kinetic inductance detector arrays of the balloon-borne OLIMPO experiment. These arrays have been designed to match the spectral bands of OLIMPO: 150, 250, 350, and 460 GHz , and they have been operated at 0.3 K and at an altitude of 37.8 km during the stratospheric flight of the OLIMPO payload, in Summer 2018. During the first hours of flight, we tuned the detectors and verified their large dynamics under the radiative background variations due to elevation increase of the telescope and to the insertion of the plug-in room-temperature differential Fourier transform spectrometer into the optical chain. We have found that the detector noise equivalent powers are close to be photon noise limited and lower than those measured on the ground. Moreover, the data contamination due to primary cosmic rays hitting the arrays is less than 3% for all the pixels of all the arrays and less than 1% for most of the pixels. These results can be considered the first step of KID technology validation in a representative space environment.

Large radio and mm–wave telescopes use very sensitive detectors requiring cryogenic cooling to reduce detector noise. Pulse Tubes (PT) cryocoolers are widely used to reach temperatures of a few K, defining the base temperature of further sub–K stages. This technology represents an effective solution for continuous operation, featuring high stability and reduced vibration levels on the detectors. However, the compressor used to operate the PT is a significant source of microphonics and electrical noise, making its use at the focus of large steerable telescopes not advisable. This calls for long flexible helium lines between the compressor, operated at the base of the radio telescope, and the cold–head, mounted in the receivers cabin with the receiver detectors. The distance between the receiver cabin and the base can be >100 m long for large radio telescopes. In the framework of our development of the MIllimetric Sardinia radio Telescope Receiver based on Array of Lumped elements kids (MISTRAL), a W–band camera working at the Gregorian focus of the 64 m aperture Sardinia Radio Telescope (SRT) with an array of Lumped Elements Kinetic Inductance Detectors (LEKID), we have developed a cryogenic system based on a PT refrigerator as the first cooling stage. Here we describe the MISTRAL cryogenic system and focus on the validation of the use of a commercial PT Cryocooler with 100 m helium lines running from the cold head to the compressor unit. The configuration allows us to operate the 0.9 W PT reaching below 4.2 K with 0.5 W dissipation.

The MIllimetric Sardinia radio Telescope Receiver based on Array of Lumped elements KIDs, MISTRAL, is a cryogenic W-band (77–103 GH) LEKID camera which will be integrated at the Gregorian focus of the 64 m aperture Sardinia Radio Telescope, in Italy, in Autumn 2022. This instrument, thanks to its high angular resolution ( ∼ 13 arcsec ) and the wide instantaneous field of view ( ∼ 4 arcmin ), will allow continuum surveys of the mm-wave sky with a variety of scientific targets, spanning from extragalactic astrophysics to solar system science. In this contribution, we will describe the design of the MISTRAL camera, with a particular focus on the optimisation and test of a prototype of the focal plane.

In this paper, we present beam pattern tests performed on the SWIPE multi-mode bolometric detector pixel assembly. A 20-mm-aperture horn is coupled to a large detector absorber (10 mm diameter) with a TES sensor located on the side. The pixel assembly has been tested at the bolometer base temperature of 340 mK, inside a custom cryogenic test bed, looking at a Gunn oscillator (128 GHz) located in the far field. We developed a custom cryogenic neoprene absorber, in addition to the stack of standard metal meshes low-pass filters, to reduce the background on the detector at a level similar to the one expected in flight, allowing to measure the main beam of the pixel assembly. The measured FWHM is 21 ∘ , slightly narrower than the expected one (24 ∘ ), due to vignetting produced by the filters stack.

We describe the development of a W-band lumped element kinetic inductance detector array for application in large ground-based telescopes, like the Sardinia radio telescope. Based on the previous studies, we use a Ti/Al bi-layer film (10 nm thick Ti + 25 nm thick Al) for the resonators, to cover frequencies greater than 65 GHz. Optical simulations have been performed using ANSYS HFSS software suite, to optimize the absorber geometry, the illumination configuration, and the thickness of the dielectric substrate. Simulations suggest that the best geometry of the absorber is a front-illuminated third-order Hilbert curve, with a Si substrate 235 μ m thick, coupled to a single-mode circular waveguide. Electrical simulations have been performed using SONNET, to complete the design of the detectors by choosing the size of the capacitor, the bias coupling, and the feedline. In addition, the electrical simulations allow us to verify the lumped condition, to tune the feedline impedance and resonant frequencies, to constrain the coupling quality factor, and to minimize the electrical cross-talk between different pixels of the same array.

We are developing a lumped element kinetic inductance detector (LEKID) array which can operate in the W-band (75 - 110 GHz) in order to perform ground-based cosmic microwave background (CMB) and mm-wave astronomical observations. The W-band is close to optimal in terms of contamination of the CMB from Galactic synchrotron, free-free, and thermal interstellar dust. In this band, the atmosphere has very good transparency, allowing interesting ground-based observations with large ( > 30 m) telescopes, achieving high angular resolution ( < 0.4 arcmin). In this work we describe the startup measurements devoted to the optimization of a W-band camera/spectrometer prototype for large aperture telescopes like the 64-m Sardinia Radio Telescope. In the process of selecting the best superconducting film for the LEKID, we characterized a 40-nm-thick aluminum 2-pixel array. We measured the minimum frequency which can break CPs (i.e., h ν = 2 Δ T c = 3.5 k B T c ) obtaining ν = 95.5 GHz, which corresponds to a critical temperature of 1.31 K. This is not suitable to cover the entire W-band. For an 80-nm layer the minimum frequency decreases to 93.2 GHz, which corresponds to a critical temperature of 1.28 K; this value is still suboptimal for W-band operation. Further increase of the Al film thickness results in bad performance of the detector. We have thus considered a Titanium–Aluminum bi-layer [10-nm-thick Ti + 25-nm-thick Al, already tested in other laboratories (Catalano et al. in Astron Astrophys 580:A15, 2015 )], for which we measured a critical temperature of 820 mK and a cut-on frequency of 65 GHz, so this solution allows operation in the entire W-band.