Monoclonal antibody humanness score and its applications

BACKGROUND: Monoclonal antibody therapeutics are rapidly gaining in popularity for the treatment of a myriad of diseases, ranging from cancer to autoimmune diseases and neurological diseases. Multiple forms of antibody therapeutics are in use today that differ in the amount of human sequence present in both the constant and variable regions, where antibodies that are more human-like usually have reduced immunogenicity in clinical trials. RESULTS: Here we present a method to quantify the humanness of the variable region of monoclonal antibodies and show that this method is able to clearly distinguish human and non-human antibodies with excellent specificity. After creating and analyzing a database of human antibody sequences, we conducted an in-depth analysis of the humanness of therapeutic antibodies, and found that increased humanness score is correlated with decreased immunogenicity of antibodies. We further discovered a surprisingly similarity in the immunogenicity of fully human antibodies and humanized antibodies that are more human-like based on their humanness score. CONCLUSIONS: Our results reveal that in most cases humanizing an antibody and confirming the humanness of the final form may be sufficient to eliminate immunogenicity issues to the same extent as using fully human antibodies. We created a public website to calculate the humanness score of any input antibody sequence based on our human antibody database. This tool will be of great value during the preclinical drug development process for new monoclonal antibody therapeutics

A Transcriptional Program Mediating Entry into Cellular Quiescence

The balance of quiescence and cell division is critical for tissue homeostasis and organismal health. Serum stimulation of fibroblasts is well studied as a classic model of entry into the cell division cycle, but the induction of cellular quiescence, such as by serum deprivation (SD), is much less understood. Here we show that SS and SD activate distinct early transcriptional responses genome-wide that converge on a late symmetric transcriptional program. Several serum deprivation early response genes (SDERGs), including the putative tumor suppressor genes SALL2 and MXI1, are required for cessation of DNA synthesis in response to SD and induction of additional SD genes. SDERGs are coordinately repressed in many types of human cancers compared to their normal counterparts, and repression of SDERGs predicts increased risk of cancer progression and death in human breast cancers. These results identify a gene expression program uniquely responsive to loss of growth factor signaling; members of SDERGs may constitute novel growth inhibitors that prevent cancer

Quark-Antiquark Bound States in the Relativistic Spectator Formalism

The quark-antiquark bound states are discussed using the relativistic spectator (Gross) equations. A relativistic covariant framework for analyzing confined bound states is developed. The relativistic linear potential developed in an earlier work is proven to give vanishing meson$\to$ $q+\bar{q}$ decay amplitudes, as required by confinement. The regularization of the singularities in the linear potential that are associated with nonzero energy transfers (i.e. $q^2=0,q^{\mu}\neq0$) is improved. Quark mass functions that build chiral symmetry into the theory and explain the connection between the current quark and constituent quark masses are introduced. The formalism is applied to the description of pions and kaons with reasonable results.Comment: 31 pages, 16 figure

Validation of Kalman Filter alignment algorithm with cosmic-ray data using a CMS silicon strip tracker endcap

A Kalman Filter alignment algorithm has been applied to cosmic-ray data. We discuss the alignment algorithm and an experiment-independent implementation including outlier rejection and treatment of weakly determined parameters. Using this implementation, the algorithm has been applied to data recorded with one CMS silicon tracker endcap. Results are compared to both photogrammetry measurements and data obtained from a dedicated hardware alignment system, and good agreement is observed.Comment: 11 pages, 8 figures. CMS NOTE-2010/00

From Current to Constituent Quarks: a Renormalization Group Improved Hamiltonian-based Description of Hadrons

A model which combines the perturbative behavior of QCD with low energy phenomenology in a unified framework is developed. This is achieved by applying a similarity transformation to the QCD Hamiltonian which removes interactions between the ultraviolet cutoff and an arbitrary lower scale. Iteration then yields a renormalization group improved effective Hamiltonian at the hadronic energy scale. The procedure preserves the standard ultraviolet behavior of QCD. Furthermore, the Hamiltonian evolves smoothly to a phenomenological low energy behavior below the hadronic scale. This method has the benefit of allowing radiative corrections to be directly incorporated into nonperturbative many-body techniques. It is applied to Coulomb gauge QCD supplemented with a low energy linear confinement interaction. A nontrivial vacuum is included in the analysis via a Bogoliubov-Valatin transformation. Finally, the formalism is applied to the vacuum gap equation, the quark condensate, and the dynamical quark mass.Comment: 36 pages, RevTeX, 5 ps figures include

Nonperturbative Renormalization and the QCD Vacuum

We present a self consistent approach to Coulomb gauge Hamiltonian QCD which allows one to relate single gluon spectral properties to the long range behavior of the confining interaction. Nonperturbative renormalization is discussed. The numerical results are in good agreement with phenomenological and lattice forms of the static potential.Comment: 23 pages in RevTex, 4 postscript figure

Energy dependence of exclusive J/ photoproduction off protons in ultra-peripheral p-Pb collisions at sNN=5.02 TeV mathrmJ/psimathrm J/psi J / ψ photoproduction off protons in ultra-peripheral p–Pb collisions at sqrtsmathrmscriptscriptstyleNN=5.02sqrts_mathrm scriptscriptstyle NN = 5.02 s NN = 5.02 TeV

The ALICE Collaboration has measured the energy dependence of exclusive photoproduction of J/ vector mesons off proton targets in ultra-peripheral p-Pb collisions at a centre-of-mass energy per nucleon pair =5.02 TeV. The e+e- and +- decay channels are used to measure the cross section as a function of the rapidity of the J/ in the range -2.5<2.7, corresponding to an energy in the p centre-of-mass in the interval 40<550 GeV. The measurements, which are consistent with a power law dependence of the exclusive J/ photoproduction cross section, are compared to previous results from HERA and the LHC and to several theoretical models. They are found to be compatible with previous measurements

Particle creation via relaxing hypermagnetic knots

We demonstrate that particle production for fermions coupled chirally to an Abelian gauge field like the hypercharge field is provided by the microscopic mechanism of level crossing. For this purpose we use recent results on zero modes of Dirac operators for a class of localized hypermagnetic knots.Comment: Latex, 10 pages, no figure