Nektar Therapeutics

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

University of Connecticut

Bhalchandra V Joshi

Neel Kumar Anand

Bo-Liang Deng

Zhongxu Ren

Haiying Cai

Saul Kivimae

Kenneth Alan Jacobson

Brian Bray

Seoju Lee

Patrick L Spence

Jonathan Zalevsky

Takahiro Miyazaki

Anthony O Chong

Shaoyong Nie

Samuel Mcmanus

Antoni Kozlowski

Samuel P McManus

Bruce T Liang

Susanna Tchilibon

John R Handley

Anthony G Schaefer

Patrick Spence

Mary Tagliaferri

David Swallow

Greg Lavaty

Sachin Tipnis

Rhoneil L Pena

Werner Rubas

Thatikonda Santhosh Kumar

Marlene Hennessy

Bruce Liang

Thatikonda Santosh Kumar

Provided are multi-arm polymer conjugates of Toll-Like Receptor (“TLR”) agonists such as TLR 7/8 agonists, as well as related compositions, and methods of making and using such conjugates. Exemplary conjugates are encompassed by Formula I: or a pharmaceutically acceptable salt form thereof, where R, taken together with each Q, is a residue of a polyol, polythiol, or polyamine bearing from 3 to about 50 hydroxyl, thiol, or amino groups; each Q is a linker selected from oxygen, sulfur and —NH; each POLY is independently a water-soluble, non-peptidic polymer; each Xis independently a linkage-containing spacer moiety; q is a positive integer from 3 to about 50; and each TLR 7/8 AG is a Toll-like receptor 7/8 agonist. Also provided is a method of administering to a patient having cancer (a) an IL-2Rβ-activating amount of a long-acting, IL-2Rβ-selective agonist; and (b) a Toll-like receptor agonist such as a conjugate as described above, as well as related compositions, kits and methods.

Multi-arm polymer conjugates of TLR agonist compounds and related immunotherapeutic treatment methods

Provided is a method of administering to a patient having cancer: (a) a 4-1BB agonist; (b) an IL-2Rβ-activating amount of a long-acting, IL-2Rβ-selective agonist; and/or (c) a toll-like receptor agonist, as well as related compositions, kits and compositions.

Immunotherapeutic tumor treatment method

Disclosed herein are methods in the field of cancer immunotherapy that involve the treatment of a subject having cancer by administering to the subject a toll-like receptor 7/8 (TLR7/8) agonist in combination with a long-acting IL-2Rβ-biased agonist and a programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) axis inhibitor, and related compositions, dosage forms, and kits.

Provided are multi-arm polymer conjugates of Toll-Like Receptor ('TLR') agonists such as TLR 7/8 agonists, as well as related compositions, and methods of making and using such conjugates. Exemplary conjugates are encompassed by Formula I: (I) or a pharmaceutically acceptable salt form thereof, where R, taken together with each Q, is a residue of a polyol, polythiol, or polyamine bearing from 3 to about 50 hydroxyl, thiol, or amino groups; each Q is a linker selected from oxygen, sulfur and &#x2014;NH; each POLY is independently a water-soluble, non-peptidic polymer; each Xr is independently a linkage-containing spacer moiety; q is a positive integer from 3 to about 50; and each TLR 7/8 AG is a Toll-like receptor 7/8 agonist. Also provided is a method of administering to a patient having cancer (a) an IL-2R&#x3b2;-activating amount of a long-acting, IL-2R&#x3b2;-selective agonist; and (b) a Toll-like receptor agonist such as a conjugate as described above, as well as related compositions, kits and methods.RQ-POLY-Xr-TLR7/8 AG)&#x2003;&#x2003;(I)

Among other aspects, provided herein is a mixed-acid salt of a water-soluble polymer-drug conjugate, along with related methods of making and using the same. The mixed-salt acid salt is stably formed, and appears to be more resistant to hydrolytic degradation than the corresponding predominantly pure acid salt or free base forms of the polymer-drug conjugate. The mixed acid salt is reproducibly prepared and recovered, and provides surprising advantages over non-mixed acid salt forms of the water-soluble polymer drug conjugate.

Acid salt forms of polymer-drug conjugates and alkoxylation methods

Among other aspects, provided herein is a hydrohalide salt of a multi-arm water-soluble polyethylene glycol-drug conjugate, along with related methods of making and using the same. The hydrohalide salt is stably formed, and appears to be more resistant to hydrolytic degradation than the corresponding free base form of the conjugate.

Salt form of a multi-arm polymer-drug conjugate

Phosphonate and phosphinate N-methanocarba derivatives of AMP including their prodrug analogs are described. MRS2339, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) ring system in place of ribose, activates P2X receptors, ligand-gated ion channels. Phosphonate analogs of MRS2339 were synthesized using Michaelis-Arbuzov and Wittig reactions, based on the expectation of increased half-life in vivo due to the stability of the C&#x2014;P bond. When administered to calsequestrin-overexpressing mice (a genetic model of heart failure) via a mini-osmotic pump (Alzet), some analogs significantly increased intact heart contractile function in vivo, as assessed by echocardiography-derived fractional shortening (FS) as compared to vehicle-infused mice. The range of carbocyclic nucleotide analogs for treatment of heart failure has been expanded.

Compositions and methods to treat cardiac diseases

Disclosed are (N)-methanocarba adenine nucleosides of the formula: as highly potent Aadenosine receptor agonists, pharmaceutical compositions comprising such nucleosides, and a method of use of these nucleosides, wherein R-Rare as defined in the specification. These nucleosides are contemplated for use in the treatment a number of diseases, for example, inflammation, cardiac ischemia, stroke, asthma, diabetes, and cardiac arrhythmias. The invention also provides compounds that are agonists of both Aand Aadenosine receptors for use in cardioprotection.

Purine derivatives as A3 and A1 adenosine receptor agonists

Growing community of inventors

Madison, AL, United States of America

Bhalchandra V Joshi