US 2020/0048334 A1 · NOVEL CARBOHYDRATE ANTIBODIES, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF

Abstract

The present invention provides antibodies or the antigen-binding portion thereof to a tumor-associate carbohydrate antigen. Also disclosed herein are pharmaceutical compositions and methods for the inhibition of cancer cells in a subject in need thereof. The pharmaceutical compositions comprise an antibody or an antigen-binding portion thereof and at least one pharmaceutically acceptable carrier.

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Claims19

Dependent claims

1-25. (canceled)

A method for inhibiting proliferation of a cancer cell, comprising:

contacting the cancer cell with an effective amount of an antibody, or antigen-binding portion thereof, that binds to a carbohydrate antigen, wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region comprising:
a heavy chain complementarity determining region HC-CDR1 selected from the group consisting of:
(i) SEQ ID NO:
1,
(ii) SEQ ID NO:
1 wherein amino acid residue 3 is substituted with an arginine (S028R), and
(iii) SEQ ID NO:
1 wherein amino acid residue 6 is substituted with an arginine (T031R),
a heavy chain complementarity determining region HC-CDR2 selected from the group consisting of:
(i) SEQ ID NO:
2,
(ii) SEQ ID NO:
2 wherein amino acid residue 6 is substituted with a glycine (D057G), and
(iii) SEQ ID NO:
2 wherein amino acid residue 12 is substituted with a tyrosine (P063Y),
a heavy chain complementarity determining region HC-CDR3 selected from the group consisting of:
(i) SEQ ID NO:
3, and
(ii) SEQ ID NO:
3 wherein amino acid residue 6 is substituted with an arginine (D105R),
a light chain complementarity determining region LC-CDR1 selected from the group consisting of:
(i) SEQ ID NO:
7,
(ii) SEQ ID NO:
7 wherein amino acid residue 1 is substituted with a tryptophan (R024W), and
(iii) SEQ ID NO:
7 wherein amino acid residue 9 is substituted with a glutamine (M032Q),
a light chain complementarity determining region LC-CDR2 selected from the group consisting of:
(i) SEQ ID NO:
8,
(ii) SEQ ID NO:
8 wherein amino acid residue 1 is substituted with a glycine (A049G), and
(iii) SEQ ID NO:
8 wherein amino acid residue 5 is substituted with a lysine (L053K), and
a light chain complementarity determining region LC-CDR3 selected from the group consisting of:
(i) SEQ ID NO:
9, and
(ii) SEQ ID NO:
9 wherein amino acid residue 6 is substituted with an arginine (N093R),
wherein the antibody, or an antigen-binding portion thereof comprises at least one of the amino acid substitutions in a CDR region selected from the group consisting of S028R, T031R, D057G, P063Y, D105R, R024W, M032Q, A049G, L053K and N093R.

37 more elements

A method for treating cancer, comprising:

administering to a subject in need of such treatment an effective amount of a pharmaceutical composition comprising:
an antibody, or antigen-binding portion thereof, that binds to a carbohydrate antigen;
and
a pharmaceutical acceptable carrier,
wherein the antibody, or antigen-binding portion thereof, comprises a heavy chain variable region and a light chain variable region comprising:
a heavy chain complementarity determining region HC-CDR1 selected from the group consisting of:
(i) SEQ ID NO:
1,
(ii) SEQ ID NO:
1 wherein amino acid residue 3 is substituted with an arginine (S028R), and
(iii) SEQ ID NO:
1 wherein amino acid residue 6 is substituted with an arginine (T031R),
a heavy chain complementarity determining region HC-CDR2 selected from the group consisting of:
(i) SEQ ID NO:
2,
(ii) SEQ ID NO:
2 wherein amino acid residue 6 is substituted with a glycine (D057G), and
(iii) SEQ ID NO:
2 wherein amino acid residue 12 is substituted with a tyrosine (P063 Y1),
a heavy chain complementarity determining region HC-CDR3 selected from the group consisting of:
(i) SEQ ID NO:
3, and
(ii) SEQ ID NO:
3 wherein amino acid residue 6 is substituted with an arginine (D105R),
a light chain complementarity determining region LC-CDR1 selected from the group consisting of:
(i) SEQ ID NO:
7,
(ii) SEQ ID NO:
7 wherein amino acid residue 1 is substituted with a tryptophan (R024W), and
(iii) SEQ ID NO:
7 wherein amino acid residue 9 is substituted with a glutamine (M032Q),
a light chain complementarity determining region LC-CDR2 selected from the group consisting of:
(i) SEQ ID NO:
8,
(ii) SEQ ID NO:
8 wherein amino acid residue 1 is substituted with a glycine (A049G), and
(iii) SEQ ID NO:
8 wherein amino acid residue 5 is substituted with a lysine (L053K), and
a light chain complementarity determining region LC-CDR3 selected from the group consisting of:
(i) SEQ ID NO:
9, and
(ii) SEQ ID NO:
9 wherein amino acid residue 6 is substituted with an arginine (N093R),
wherein the antibody, or an antigen-binding portion thereof, comprises at least one of the amino acid substitutions in a CDR region selected from the group consisting of S028R, T031R, D057G, P063Y, D105R, R024W, M032Q, A049G, L053K and N093R.

41 more elements

Dependencies are inferred from the claim text.

Description12,573 words

Summary1,317 words

#The present invention relates to modified antibodies to tumor-associated carbohydrate antigens, having some specific amino acid substitutions relative to the unmodified antibodies, as well as the unmodified antibodies. The present invention also relates to the use of these antibodies in the treatment, prevention or management of diseases or disorders, such as cancer or the inhibition of cancer cells.

#Numerous surface carbohydrates are expressed in malignant tumor cells. For example,

#Globo H (Fuc α1→2Galβ1→3GalNAcβ1→3Gal a1→4Galβ1→4Glc) has been shown to be overexpressed on a variety of epithelial cancers and is associated with tumor aggressiveness and poor prognosis in breast cancer and small cell lung carcinoma.

Brief description of the drawings8 figures

#FIG. 1A illustrates the amino acid sequence of an exemplary embodiment of the heavy chain variable region of the unmodified humanized antibody (SEQ ID NO. 13). FIG. 1B illustrates the amino acid sequence of an exemplary embodiment of the light chain variable region of the unmodified humanized antibody (SEQ ID NO. 14).

#FIG. 2 illustrates the optical density (OD45onm) of one exemplary embodiment of the chimeric antibody (Heavy chain: SEQ ID NO. 57 and Light chain: SEQ ID NO. 58) and one exemplary embodiment of the humanized antibody (Heavy chain: SEQ ID NO. 13 and Light chain: SEQ ID NO. 14).

#FIG. 3 illustrates schematically the process for Comprehensive Positional Evolution and Combinatorial Protein Synthesis.

Detailed description10,880 words

#As used herein, the articles “a” and “an” refer to one or more than one (i.e., at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

#An “effective amount,” as used herein, refers to a dose of the antibody or pharmaceutical composition that is sufficient to reduce the symptoms and signs of cancer, such as weight loss, pain and palpable mass, which is detectable, either clinically as a palpable mass or radiologically through various imaging means. The term “effective amount” and “therapeutically effective amount” are used interchangeably.

#The term “subject” can refer to a vertebrate having cancer or to a vertebrate deemed to be in need of cancer treatment. Subjects include all warm-blooded animals, such as mammals, such as a primate, and, more preferably, a human. Non-human primates are subjects as well. The term subject includes domesticated animals, such as cats, dogs, etc., livestock (for example, cattle, horses, pigs, sheep, goats, etc.) and laboratory animals (for example, mouse, rabbit, rat, gerbil, guinea pig, etc.). Thus, veterinary uses and medical formulations are contemplated herein.

Facts

Application

16/547,009Filed 21 Aug 2019

Priority

7 Oct 2015

Published

13 Feb 2020

Term ends

Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07K 16/18
Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies: against material from animals or humans
A61P 35/00
Antineoplastic agents
C07K 16/30
Against receptors, cell surface antigens or cell surface determinants: from tumour cells
C07K 16/44
Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies: against material not provided for elsewhere , e.g. haptens, metals, DNA, RNA,…

Family

Application62/238,680Us provisional application · filed 7 Oct 2015

Application15/288,562Division · filed 7 Oct 2016

Application16/547,009Division

US 10,501,532 B2Related patent

US 11,236,154 B2Related patent

US 2017/0101462 A1Published application

US 2020/0048334 A1This patent

From the US filing history. Foreign family members aren’t listed.

Novel carbohydrate antibodies, pharmaceutical compositions and uses thereof

Life of this patent

Novel carbohydrate antibodies, pharmaceutical compositions and uses thereof

Life of this patent

Life of this patent

Abstract

Drawings

Drawings

Claims19

Description12,573 words

Drawings

Classification14 codes

Life of this patent

Description12,573 words