Agency for Science, Technology and Research

Cyclacel Limited

The United States of America, As Represented by the Secretary, Department of Health and Human Services

University of Dundee

Masaryk Memorial Cancer Institute

National University of Singapore

Singapore Health Services Pte Ltd

University Court of the University of Dundee

University Court of the University of St. Andrews

Cancer Research Campaign Technology Limited

Merck Sharp + Dohme Corp.

Msd International Gmbh

David Philip Lane

Curtis C Harris

Jean-Christophe Bourdon

Borivoj Vojtesek

Izumi Horikawa

Kaori Fujita

Le-Ann Hwang

Xin Yu Koh

Lynne Suzanne Cox

David Moore Glover

Robin Fahraeus

Liew Oi Wah

Tr Kanaga Sabapathy

Emma Warbrick

Pascal Furet

Carlos Garcia-Echeverria

Nicholas James Westwood

Heinz-Kurt Hochkeppel

Chandra Shekhar Verma

Sonia Lain

Charles William Johannes

Christopher John Brown

Tsz Ying Yuen

Patrick Chène

Pietro Aronica

Srinivasaraghavan Kannan

Terrence Patrick Herbert

Kathryn Lindsay Ball

Steven Michael Picksley

Angelika Böttger

Volker Böttger

Yaw Sing Tan

Christopher Gregory Proud

Shuxian Julin Wong

Thomas Joseph

Fernando Jose Ferrer Gago

Fernando J Ferrer

Christoper J Brown

Anthony W Partridge

The invention relates to methods for producing an antibody which is specific for a mutant p53 polypeptide over wildtype p53 polypeptide, comprising using as an immunogen a peptide or polypeptide comprising: (i) an antigen sequence, comprising an amino acid sequence of the mutant p53 polypeptide including the mutation and at least one amino acid immediately adjacent to the mutation, and (ii) a scaffold sequence for providing the antigen sequence in a solvent-accessible configuration. Also provided are antibodies produced by such methods, and uses thereof.

Anti-p53 antibodies

The invention relates to methods for producing an antibody which is specific for a mutant p53 polypeptide over wildtype p53 polypeptide, comprising using the mutant p53 polypeptide as an immunogen wherein the polypeptide comprises: (i) an antigen sequence, comprising an amino acid sequence of the mutant p53 polypeptide including the mutation and at least one amino acid immediately adjacent to the mutation, and (ii) a scaffold sequence for providing the antigen sequence in a solvent-accessible configuration, in particular wherein the scaffold sequence is thioredoxin. In the specific embodiments, antibodies against mutant p53 comprising R175H, R248Q or R273H are generated. Also disclosed are the uses of the antibodies for diagnosis, prognosis and stratification of patient groups and further encompasses the use of antibodies for imaging and treatment of cancer.

The present invention relates to non-membrane disruptive and p53 activating stapled peptides, as well as methods of treatment of cancer involving the use of these peptides. In one embodiment, the peptide comprises or consist of the amino acid sequence of TSFXaaEY-WXaaLLXaa, where Xaais (R)-2-(7'-octenyl)alanine or derivative thereof, or is (R)-2-(4&#x2032;-pentenyl)alanine or derivative thereof; and Xaaand Xaaare independently any type of amino acid or modified amino acid. In another embodiment, the peptide comprising or consisting of the amino acid sequence of TSFXaaEYW XaaLLXaaENXaa, wherein Xaaand Xaaare any type of amino acid or modified amino acid; Xaais S, or P, or (S)-2-(4&#x2032;-pentenyl)alanine or a derivative of (S)-2-(4&#x2032;-pentenyl)alanine; and wherein Xaais F or Y.

Non-membrane disruptive P53 activating stapled peptides

Disclosed are monoclonal antibodies that bind specifically to macrophage stimulating protein receptor (or RON&#x2014;Recepteur d' Origine Nantais). Also provided are the chimeric antigen receptors, bispecific antibodies, bivalent antibodies and biTE thereof, as well as pharmaceutical compositions and uses of said antibodies for the treatment of cancer and fibrosis and an ex vivo method of evaluating the status of a cancer patient using said antibodies. In particular, two monoclonal antibodies, 7G8 and 6D4, demonstrating good therapeutic efficacy in inhibiting tumour growth in human xenograft mice models and sensitivity in human xenograft mouse tumour imaging models are provided.

Macrophage stimulating protein receptor (or RON&#x2014;recepteur d'Origine Nantais) antibodies and uses thereof

Antibodies specifically binding an epitope comprised in the &#x3b1;-chain of c-Met, modifications, compositions and uses thereof are disclosed herein.

mAB 2 anti-Met antibody

The present invention provides methods and compositions for modulating cell senescence and cell proliferation using isoforms of the p53 tumor suppressor protein. The methods and compositions of the invention find use in inhibiting cancer cell growth or in generating populations of cells for tissue regeneration through the modulation of cell senescence and proliferation.

Therapeutic applications of p53 isoforms in regenerative medicine, aging and cancer

The invention provides compounds according to formula (I): (wherein X, Y, Z1 R1, R2, R3, Ar and Ar' are as defined herein), and physiologically acceptable salts, solvates, esters or amides thereof, pharmaceutical compositions comprising these compounds and the compounds for use in medicine, for example for the treatment or prophylaxis of diseases involving cell proliferation, such as cancer, and for the treatment or prophylaxis of other diseases. 

Aroyl thiourea derivatives

Therapeutic applications of P53 isoforms in regenerative medicine, aging and cancer

We claim a therapeutic method of inducing programmed cell death comprising administering to a recipient a peptide of 10&#x2013;25 amino acids, comprising the sequence: (KR)xxYxxx(F/Q)L(L/M) wherein x is any amino acid.

Use of peptides

The present invention relates to compounds capable of binding to the oncogene protein MDM2, processes for the preparation of such compounds, pharmaceutical preparations comprising such compounds, and uses of said compounds, e.g. in the therapeutic (including prophylactic) treatment of an animal or especially of the human body. The present further relates to methods of and compounds for inhibiting the growth of tumor cells which comprise the wild type p53 suppressor by interfering with the interaction between human p53 and human MDM2.

Inhibitors of the interaction between P53 and MDM2

p21interacts with cyclin D1 and Cdk4. Peptide fragments of p21 inhibit the interaction and/or affect Cdk4 activity. The peptides, derivative peptides and non-peptidyl mimetics thereof are useful in affecting activity of Cdk4, such as RB phosphorylation, and cellular proliferation, indicative of therapeutic usefulness in treatment of tumours and other hyperproliferative disorders. Assay and screening methods allow identification of such modulators, especially inhibitors, of Cdk4 activity.

Methods and means for inhibition of Cdk4 activity

PCNA binding substance

The present disclosure identifies substances having the property of binding to cyclin dependent kinase (cdk) comprising: (i) a peptide including amino acid residue 84 to 103 of full length p16 protein, or an active portion or derivative thereof; or (ii) a functional mimetic of the fragment, active portion or derivative; the substance excludes full length p16, p15, p18 and p19 proteins. These substances are useful in tumor suppression by inhibiting the phosphorylation of Rb protein. Also described herein is the resolution of the amino acid motifs responsible for binding cdks, an FLD motif, corresponding to amino acid residues 90 to 92 of full length p16 protein, and an LVVL motif, corresponding to amino acid residues 94 to 97 of full length p16 protein. The substances disclosed herein can be used in the treatment of hyperproliferative disorders and to screen and design molecules having the similar properties.

Cyclin dependent kinase binding peptides

Substances are disclosed which have the property of binding to PCNA, the substances comprising (i) a fragment of the p21,protein including residues 141 to 160 of the p21,amino acid sequence, or an active portion or derivative thereof; or (ii) functional mimetics of these protein fragments. In particular, the PCNA binding activity is shown to lie within the sequence motif OTSMTDFY, with the residues shown in bold being critical for PCNA binding, with those underlined being important. These substances are useful in the treatments of disorders in which PCNA is implicated, e.g. hyperproliferative disorders such as cancer and psoriasis, the substances binding to PCNA to inactivate it or functionally deplete its level. Also disclosed is the use of a yeast two hybrid screening technique for screening candidate peptides for binding to PCNA.

Identification of the P21WaF1-PCNA interaction site and therapeutic applications thereof

Growing community of inventors

Singapore, Singapore

David Philip Lane