Anti-nucleolin antibodies

Abstract

The present disclosure provides anti-nucleolin antibodies, methods of producing anti-nucleolin antibodies, and cells producing anti-nucleolin antibodies. Also provided are methods of using anti-nucleolin antibodies in treating malignant and non-malignant diseases.

1 - 81 . (canceled) 
     
     
         82 . A host cell that comprises the nucleic acid of  claim 132 . 
     
     
         83 - 115 . (canceled) 
     
     
         116 . An immunoconjugate, wherein the immunoconjugate comprises an antigen binding agent linked to a therapeutic agent, and wherein the antigen binding agent comprises the isolated antibody or fragment that binds to human nucleolin and comprises:
 a heavy chain CDR1 having an amino acid sequence that comprises   SEQ ID NO:42;   a heavy chain CDR2 having an amino acid sequence that comprises YIS;   a heavy chain CDR3 having an amino acid sequence that comprises DM;   a light chain CDR1 having an amino acid sequence that comprises SEQ ID NO:65;   a light chain CDR2 having an amino acid sequence that comprises SEQ ID NO:54; and   a light chain CDR3 having an amino acid sequence that comprises SEQ ID NO:66.   
     
     
         117 . The immunoconjugate of  claim 116 , wherein the immunoconjugate is a fusion protein, and wherein the therapeutic agent is a polypeptide. 
     
     
         118 . The immunoconjugate of  claim 116 , wherein the antigen binding agent is a bispecific antibody. 
     
     
         119 . The immunoconjugate of  claim 116 , wherein the antigen binding agent is a probody. 
     
     
         120 . The immunoconjugate of  claim 119 , wherein the probody comprises an antigen-binding region that is activated by a tumor cell. 
     
     
         121 . The immunoconjugate of  claim 120 , wherein the antigen-binding region comprises a peptide linked to the N-terminus of a light chain through a protease cleavable linker. 
     
     
         122 . The immunoconjugate of  claim 116 , wherein the antigen binding agent is linked covalently, noncovalently, or recombinantly to the therapeutic agent. 
     
     
         123 . The immunoconjugate of  claim 116 , wherein the therapeutic agent is a cytotoxic agent. 
     
     
         124 . The immunoconjugate of  claim 123 , wherein the cytotoxic agent is doxorubicin, calicheamicin, auristatin, maytansinoid, brentuximab vedotin, tubulysins, duocarmycins, camptothecin, SN-38, pyrrolobenzodiazepine, methotrexate, α-amanitin, ansamitocin, or any combination thereof. 
     
     
         125 . The immunoconjugate of  claim 116 , wherein the therapeutic agent is an immune stimulating agent. 
     
     
         126 . The immunoconjugate of  claim 125 , wherein the therapeutic agent is interleukin-2 (IL-2), an immunostimulatory nucleic acid molecule, granulocyte macrophage colony-stimulating factor, resiquimod, Gardiquimod, phycocyanobilin, romiplostim, eltrombopag, or any combination thereof. 
     
     
         127 . A pharmaceutical composition that comprises the immunoconjugate of  claim 116  and a pharmaceutically acceptable carrier. 
     
     
         128 . A method of treating a cancer, comprising administering to a subject in need thereof a pharmaceutical composition that comprises the immunoconjugate of  claim 116 . 
     
     
         129 - 130 . (canceled) 
     
     
         131 . The immunoconjugate of  claim 116 , wherein the therapeutic agent is a radionuclide. 
     
     
         132 . A nucleic acid encoding an isolated antibody or fragment thereof, wherein the isolated antibody or fragment thereof binds to human nucleolin and comprises:
 a heavy chain CDR1 having an amino acid sequence that comprises   SEQ ID NO:42;   a heavy chain CDR2 having an amino acid sequence that comprises YIS;   a heavy chain CDR3 having an amino acid sequence that comprises DM;   a light chain CDR1 having an amino acid sequence that comprises SEQ ID NO:65;   a light chain CDR2 having an amino acid sequence that comprises SEQ ID NO:54; and   a light chain CDR3 having an amino acid sequence that comprises SEQ ID NO:66.   
     
     
         133 . The isolated antibody or fragment thereof of  claim 132 , wherein the heavy chain variable region (VH) has at least 90% sequence identity to amino acid sequence SEQ ID NO:3, and wherein the light chain variable region (VL) has at least 90% sequence identity to amino acid sequence SEQ ID NO:12. 
     
     
         134 . The isolated antibody or fragment thereof of  claim 132 , wherein the heavy chain variable region (VH) has at least 95% sequence identity to amino acid sequence SEQ ID NO:3, and wherein the light chain variable region (VL) has at least 95% sequence identity to amino acid sequence SEQ ID NO:12. 
     
     
         135 . The isolated antibody or fragment thereof of  claim 132 , wherein the heavy chain variable region (VH) has at least 98% sequence identity to amino acid sequence SEQ ID NO:3, and wherein the light chain variable region (VL) has at least 98% sequence identity to amino acid sequence SEQ ID NO:12. 
     
     
         136 . The isolated antibody or fragment thereof of  claim 132 , wherein the heavy chain has at least 85% sequence identity to amino acid sequence SEQ ID NO:2 or SEQ ID NO: 14, and wherein the light chain has at least 85% sequence identity to amino acid sequence SEQ ID NO: 11. 
     
     
         137 . The isolated antibody or fragment thereof of  claim 136 , wherein the heavy chain has at least 90% sequence identity to amino acid sequence SEQ ID NO:2 or SEQ ID NO: 14, and wherein the light chain has at least 90% sequence identity to amino acid sequence SEQ ID NO: 11. 
     
     
         138 . The isolated antibody or fragment thereof of  claim 136 , wherein the heavy chain has an amino acid sequence SEQ ID NO:2 or SEO ID NO: 14, and wherein the light chain has an amino acid sequence that comprises SEQ ID NO: 11.