Other

Yale University

The United States Government as Represented by the Department of Veterans Affairs

University of California

Allegiance Corporation

Nucleus Therapeutics Pty. Ltd

Chevron Research Company

James E Hansen

Richard H Weisbart

Robert N Nishimura

Peter Lawrence Visconti

Ashvin H Desai

Jiangbing Zhou

Gary P Schroeder

Robert W Thomas

Zahra Rattray

Thomas A Doering

Peter M Glazer

James Campbell

Grace Chan

Valentina Dubljevic

Philip W Noble

Louis E Witte

Ken Horton

Paul V Oldershaw

Jan Wells

Stanley O Hutchison

Walter E Hinds

Leo E Thompson

Patrick S Lowery

Kenneth W Horton

Janice B Wells

Melissa Young

The present disclosure relates to cell penetrating anti-DNA binding proteins. Compositions comprising these binding proteins may be may be useful for delivering agents to cells and treating diseases such as cancer.

Binding proteins 1

Amino acid sequences capable of enhancing nuclear translocation are provided. Also referred to a nuclear localization signals (NLS) the sequences can be linked to or grafted into antibodies or fragments or fusion proteins thereof to enhance nuclear translocation of the antibody. Compositions and antibodies including an NLS conjugated or otherwise linked directly or indirectly to an active agent cargo are also provided. Exemplary cargo includes proteins, peptides, carbohydrates, polysaccharides, nucleic acid molecules, inorganic molecules, organic molecules, and diagnostic agents. Pharmaceutical compositions further including a pharmaceutically acceptable carrier are also provided. Methods of delivering the composition or antibody alone or with a cargo linked thereto to the nucleus of cell, methods of selecting or screening for compositions having a desired cellular activity, and methods of treating diseases and disorders are also provided.

Nuclear localization signals, compositions formed therefrom, and methods of use thereof for delivery of cargo to the nucleus

DNA-targeted nanocarriers for encapsulating an active agent and delivering it to extracellular DNA are provided. The nanocarriers, for example, polymeric particles, liposomes, and multilamellar vesicles have targeting moiety that targets DNA conjugated thereto. The targeting moiety that targets DNA is typically an antibody, or variant, fragment, or fusion protein derived therefrom that binds to DNA or nucleosomes. The targeting moiety can be a circulating autoantibody that binds DNA such as those commonly found in patients with SLE. In some embodiments, the targeting moiety is antibody 3E10 or a variant, fragment, or fusion protein derived therefrom. Pharmaceutical compositions, methods of use, and dosage regimens are also provided.

Antibody-mediated autocatalytic, targeted delivery of nanocarriers to tumors

Antibodies that penetrate cell nuclei and inhibit DNA repair or interfere with DNA metabolism are provided for treatment of cancer (both directly and by sensitizing cancer cells to DNA-damaging treatments) or inhibiting or preventing viral infection, proliferation or metabolism. The method involves treating cells with a composition containing cell-penetrating anti-DNA antibodies or derivatives thereof, alone or in combination with treatment that induces DNA damage such as DNA-damaging chemotherapy or radiation. The impact of the cell-penetrating anti-DNA antibodies or derivatives thereof is potentiated in cancer cells that are deficient in DNA repair, and the cell-penetrating anti-DNA antibodies or derivatives thereof are synthetically lethal to cancer cells with DNA repair deficiencies.

Cell-penetrating anti-DNA antibodies and uses thereof inhibit DNA repair

The invention provides for a fusion protein comprising a 3E10 Fv joined to a Hsp-70, Hsp-27, Hsp-90 or GRP-78 or portion thereof, and optionally, the 3E10 Fv comprising an amino acid sequence AGIH at its amino terminus.

Antibody-mediated transduction of heat shock proteins into living cells

Cancer cells with defects in DNA repair are highly susceptible to DNA-damaging agents, but delivery of therapeutic agents into cell nuclei can be challenging. A sub-set of autoantibodies having nucleolytic activity are capable of nuclear penetration. These antibodies can be used as therapeutic agents targeted towards DNA repair-deficient malignancies.

Cell penetrating nucleolytic antibody based cancer therapy

It has been established that cancer cells with oncogenic mutants in the small GTPase K-Ras are susceptible to antibodies that bind intracellular guanosine, but delivery of antibodies into cells can be challenging. A subset of lupus autoantibodies is associated with anti-guanosine activity, and is capable of cellular penetration. These antibodies have potential as therapeutic agents targeted towards K-Ras associated malignancies.

Cell penetrating anti-guanosine antibody based therapy for cancers with Ras mutations

The present invention provides a disposable trumpet valve tube cassette assembly, as well as, a surgical irrigation instrument that includes a probe assembly, a pump, a removable pump cartridge, and a socket. The probe assembly provides passage of fluids for irrigating the body interior and for evacuating matter from the body interior. The pump provides for pumping irrigation fluid through the probe assembly into the body interior. A pump cartridge defines a pumping chamber. Electronic control circuitry includes an electronics controller and a trumpet valve switch interface. The electronics controller includes a pulse generator that generates pulses, the duty cycle of the pulses controlling the speed of the motor. The trumpet valve switch interface is in electronic connection to a switch, the interface providing a signal to the controller.

Disposable surgical suction/irrigation trumpet valve tube cassette

A method of melting solid materials while controlling melt shape, without the expenditure of energy to melt unwanted quantities of surrounding materials, and an apparatus to effect the method. The method comprises the use of a planar starter path between electrodes so as to initiate melting and/or vitrification in a plane rather than in a discrete linear path between electrodes. Because melting is initiated along a significant portion of the linear dimension of the electrodes, creating a melted zone that is deeper than it is thick, the aspect ratio (depth 'Y'/width 'Z') of the melted mass is greater than 1.0.

Method of melting solid materials

A bicycle seat for improved comfort and performance. The bicycle seat comprises an elongated support member for supporting a rider, wherein the elongated support member includes a central portion and opposed end portions that extend outward and flare backwards and upwards relative to the central portion. The seat further comprises a left and right seat cushion immovably mounted over the elongated support member, and positioned in a V-shape configuration. The configuration of the seat provides improved rider comfort, while maintaining lateral stability for the rider.

Bicycle seat

Growing community of inventors

Guilford, CT, United States of America

James E Hansen