Cd19-binding agents and use thereof

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention discloses CD19-binding agents representing an antibody or an antigen-binding fragment containing an amino acid sequence of a variable region of a heavy chain, and an amino acid sequence of a variable region of a light chain which are bound with human CD 19 with a dissociation constant equal or less 1x10 -7M. The amino acid sequences are presented in the description. There are disclosed nucleic acid coding the heavy and/or light chain of the antibody or the antigen-binding fragment and a ligand conjugate - a therapeutic agent, or its pharmaceutically acceptable salt or solvate for treating a CD19-associated disorder in a mammal specified in a group involving CD19-expressing cancer, chronic leukaemia, B-cell lymphoma, multiple myeloma and a number of the other oncological diseases. The conjugate for treating the disorder in the mammal is used in an effective amount.

EFFECT: use of the presented antibodies or conjugate enables higher survival rate of the patients with oncological diseases expressing CD19, as well as in treating immunopathological diseases.

18 cl, 26 dwg, 8 ex

 

The text descriptions are given in facsimile form.

1. The antibody or antigennegative fragment that is specific linked with human CD19 and include the amino acid sequence of the variable region of the heavy chain, at least 90% identical to the consensus sequence SEQ ID NO: 29, SEQ ID NO: 28, SEQ ID NO: 32 or SEQ ID NO: 33; and the amino acid sequence of the variable region of the light chain, at least 90% identical to the consensus sequence SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 34 or SEQ ID NO: 35, and the antibody or antigennegative fragment associated with CD19 with a constant di the Association, equal to or less than 1×10-7M

2. The antibody or antigennegative fragment according to claim 1, where the variable region of the heavy chain comprises the amino acid sequence of (a) CDR1 (SEQ ID NO: 46), CDR2 (SEQ ID NO: 47) or CDR3 (SEQ ID NO: 48).

3. The antibody or antigennegative fragment according to claim 1, where the variable region of the light chain comprises the amino acid sequence of (a) CDR1 (SEQ ID NO: 49), CDR2 (SEQ ID NO: 50) or CDR3 (SEQ ID NO: 51).

4. The antibody or antigennegative fragment according to claim 1, where the consensus amino acid sequence of the variable region of the heavy chain is at least 90% identical to the sequence of SEQ ID NO: 29.

5. The antibody or antigennegative fragment according to claim 3, where the consensus amino acid sequence of the variable region of the light chain of at least 90% identical to the sequence of SEQ ID NO: 30.

6. The antibody or antigennegative fragment according to claim 1, where the variable region of the heavy chain comprises the amino acid sequence of SEQ ID NO: 9.

7. The antibody or antigennegative fragment according to claim 1, where the variable region of the light chain comprises the amino acid sequence of SEQ ID NO: 24.

8. The antibody or antigennegative fragment according to claim 6, where the variable region of the light chain comprises the amino acid sequence of SEQ ID NO: 24.

9. The antibody according to claim 1, comprising a constant region of human IgG.

Tie according to claim 3, comprising a constant region of human IgG.

11. The antibody according to claim 9, in which the isotype constant region of IgG is IgG1, IgG2 or IgG1V1.

12. The antibody of claim 10, in which the isotype constant region of IgG is IgG1, IgG2 or IgG1V1.

13. The antibody or antigennegative fragment according to any one of claims 1 to 12, where the antibody is conjugated.

14. Nucleic acid encoding a heavy chain and/or light chain of the antibody or antigennegative fragment according to any one of claims 1 to 11.

15. Conjugate the ligand-drug compound for the treatment of CD19-associated disorders in a subject mammal, having the following formula:

or its pharmaceutically acceptable salt or MES,
where L is a ligand unit, where the ligand unit is an antibody or antigennegative fragment according to any one of claims 1 to 13; and
(LU-D) is a group of the linker unit is the unit of medicinal compounds in which
LU is a linker unit and
D is a unit of drug compounds with cytotoxic or cytostatic activity against target cells; and
p is an integer from 1 to about 20.

16. Conjugate the ligand-drug connection 15 having the formula

where mAb is a monoclonal antibody containing the var is abelow region of the heavy chain, having the amino acid sequence of SEQ ID NO: 9, and the variable region of light chain having the amino acid sequence of SEQ ID NO: 24.

17. Conjugate the ligand-drug compound according to clause 16, in which the unit dosage of the compound has the formula DEDFor DZ:



or its pharmaceutically acceptable salt or MES, where independently at each position:
R2is C1-C20the alkyl, C2-C20alkenyl or C2-C20the quinil;
R3is H, C1-C20the alkyl, C2-C20alkenyl, C2-C20the quinil, carbocycle, -C1-C20alkylen(carbocycle), -C2-C20albaniles(carbocycle), -C2-C20akinyan(carbocycle), aryl, -C1-C20alkylene(aryl), -C2-C20albaniles(aryl), -C2-C20akinyan(aryl), - heterocycle, -C1-C20alkylen(heterocycle), -C2-C20albaniles(heterocycle) or-C2-C20akinyan(heterocycle);
R4is H, C1-C20the alkyl, C2-C20alkenyl, C2-C20the quinil, carbocycle, -C1-C20alkylen(carbocycle), -C2-C20albaniles(carbocycle), -C2-C20akinyan(what arboricola), the aryl, -C1-C20alkylene(aryl), -C2-C20albaniles(aryl), -C2-C20akinyan(aryl), - heterocycle, -C1-C20alkylen(heterocycle), -C2-C20albaniles(heterocycle) or-C2-C20akinyan(heterocycle);
R5is H or C1-C8by alkyl;
or R4and R5together form a carbocyclic ring and have the formula
-(CRaRb)s-, in which Raand Rbindependently are H, C1-C20the alkyl, C2-C20alkenyl, C2-C20the quinil or carbocycles and s is 1, 3, 4, 5 or 6;
R6is H, C1-C20the alkyl, C2-C20alkenyl or C2-C20the quinil;
R7is H, C1-C20the alkyl, C2-C20alkenyl, C2-C20the quinil, carbocycle,
-C1-C20alkylen(carbocycle), -C2-C20albaniles(carbocycle), -C2-C20akinyan(carbocycle), aryl, -C1-C20alkylene(aryl), -C2-C20albaniles(aryl), -C2-C20akinyan(aryl), - heterocycle, -C1-C20alkylen(heterocycle), -C2-C20albaniles(heterocycle) or-C2-C20akinyan(heterocycle);
each R8independently is H, OH, C1-C20the alkyl, C2-C20alkenyl, C -C20the quinil, -O-(C1-C20by alkyl), -O-(C2-C20alkenyl), -O-(C1-C20the quinil) or carbocycle;
R9is H, C1-C20the alkyl, C2-C20alkenyl or C2-C20the quinil;
R24is aryl, heterocycle or carbocycle;
R25is H, C1-C20the alkyl, C2-C20alkenyl, C2-C20the quinil, carbocycle, -O-(C1-C20by alkyl), -O-(C2-C20alkenyl), -O-(C2-C20the quinil) or
OR18in which R18is H, a protective group of hydroxyl or a direct link, where OR18represents =O;
R26is H, C1-C20the alkyl, C2-C20alkenyl or C2-C20the quinil, aryl, heterocycle or carbocycle;
R10is aryl or heterocycle;
Z is O, S, NH or NR12in which R12is C1-C20the alkyl, C2-C20alkenyl or C2-C20the quinil;
R11is H, C1-C20the alkyl, C2-C20alkenyl, C2-C20the quinil, carbocycle, -C1-C20alkylen(carbocycle), -C2-C20albaniles(carbocycle), -C2-C20akinyan(carbocycle), aryl, -C1-C20alkylene(aryl), -C2-C20albaniles(aryl), -C2-C20 akinyan(aryl), - heterocycle, -C1-C20alkylen(heterocycle), -C2-C20albaniles(heterocycle), -C2-C20akinyan(heterocycle), -(R13O)m-R14or -(R13O)m-CH(R15)2;
m is an integer from 1 to 1000;
R13is C2-C20alkylene, C2-C20Alcanena or C2-C20akinlana;
R14is H, C1-C20the alkyl, C2-C20alkenyl or C2-C20the quinil; whenever R15independently is H, COOH, (CH2)n-N(R16)2, -(CH2)n-SO3H, -(CH2)n-SO3-C1-C20by alkyl, -(CH2)n-SO3-C2-C20alkenyl or -(CH2)n-SO3-C2-C20the quinil;
whenever R16independently is H, C1-C20the alkyl, C2-C20alkenyl, C2-C20the quinil or -(CH2)n-COOH;
n is an integer from 0 to 6;
R27is H, C1-C20the alkyl, C2-C20alkenyl, C2-C20the quinil, O-(C1-C20by alkyl), -O-(C2-C20alkenyl), -O-(C2-C20the quinil), halogen, -NO2, -COOH or-C(O)OR28in which R28is H, C1-C20the alkyl, C2-C20alkenyl, C2 20
the quinil, aryl, heterocycle, -(CH2CH2O)r-H, -(CH2CH2O)r-CH3or (CH2CH2O)r-CH2CH2C(O)OH; where r is an integer from 1 to 10; and
X is -(CR292)I-, in which R29is H, C1-C20the alkyl, C2-C20alkenyl, C2-C20the quinil, and I is an integer from 0 to 10; where the specified alkyl, alkanniny, alkynylaryl, alkalinity, alkenylamine, alkynylaryl, aryl, carbocyclic and heterocyclic radicals, either individually or as part of another group are optionally substituted.

18. Conjugate the ligand-drug compound according to clause 16, where SW-associated violation is selected from the group comprising SW-expressing cancer, chronic leukemia, lymphoma or multiple myeloma; for example, acute lymphoblastic leukemia, b-cell type chronic miliitary leukemia, chronic lymphocytic leukemia, nahodkinskuju lymphoma and Hodgkin's lymphoma, b-cell lymphoma or diffuse In both lymphoma.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention discloses an isolated antibody which selectively binds to the C-end of beta-amyloid (Abeta) and is humanised or fully human. The antibody can be a single-chain antibody (scFv), a Fab fragment or a P(ab')2 fragment. The antibody is capable of preventing oligomerisation of Abeta. The invention discloses a nucleic acid sequence which codes the disclosed antibody, a vector and a host cell for producing the antibody, as well as a pharmacological composition for treating neurological disorders, particularly Alzheimer's disease. The invention provides methods for diagnosis using labelled antibodies disclosed herein and treating neurological disorders associated with abnormal accumulation and/or deposition of Abeta in the central nervous system by administering a therapeutically effective amount of a polynucleotide, vector or host cell to a subject.

EFFECT: invention enables successful application of the disclosed antibodies for therapeutic purposes and clinical application since in contrast to mouse antibodies, said antibodies are low- or nonimmunogenic when used in humans.

25 cl, 23 dwg, 1 tbl, 17 ex

FIELD: medicine.

SUBSTANCE: there are described versions of humanized monoclonal anti-factor D antibodies and their functional fragments. There are offered: a coding nucleic acid, an expression vector, as well as a cell for preparing c the antibody containing the vector. What is described is a method for preparing the anti-factor D antibody by cell culture and expressed antibody purification. Also, there are offered: an antibody composition and use of the antibody for treating disorders mediated by a complement system.

EFFECT: higher clinical effectiveness in the diseases related to excessive or uncontrolled activation of the complement system.

32 cl, 9 dwg, 4 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention discloses a human antibody or an antigen-binding antibody fragment which specifically binds human nerve growth factor (NGF) with KD in the order of 5 pM or less and does not cross-react with neurotrophin-3 (NT-3). The antibodies are effective in treating inflammatory pain, postoperative suture pain, neuropathic pain, fracture pain, osteoporotic fracture pain, postherpetic neuralgia, pain associated with osteoarthritis, rheumatoid arthritis, cancer, burns, joint pain in gout, as well as such diseases as hepatocellular carcinoma, breast cancer and hepatic cirrhosis. The invention discloses a nucleic acid coding a human antibody or its antibody-binding fragment, an expression vector containing the nucleic acid, and a method for producing the antibody or its antigen-binding fragment. The antibody or its fragment is used to create a pharmaceutical composition for treating the above diseases, as well as a drug preparation additionally containing IL-1 inhibitor, an antiepileptic drug, a cytokine antagonist and another neurotrophin.

EFFECT: specificity of human NGF binding by the antibody or its fragment according to the invention is 2-10 times higher than a binding ability of the antibody or its fragment in relation to rat's or mouse's NGF.

21 cl, 28 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a binding protein which is specific to IL-13, having 6CDR sections (three light and three heavy chains). The invention discloses a structure of an antibody based on this protein and a conjugate based on the antibody. The invention describes versions of nucleic acid which codes the antibody or structure, and an expression vector, a replication vector and cells bearing such vectors. Described is a method of producing the protein by culturing cells and proteins obtained using said method. Described are compositions based on versions of the proteins.

EFFECT: invention can be used in medicine to treat and diagnose diseases associated with IL-13 activity which negatively affects health.

50 cl, 23 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: there are described versions of polypeptides specifically binding human DR5 each of which contains CDR versions containing a high-limited variety of amino acid sequences. There are described versions of polypeptides fused with at least a portion of protein, viral envelopes specifically binding human DR5. There are offered: a coding nucleic acid, an expression vector, as well as a cell for polypeptide expression containing the vector. What is also described is a method for producing the polypeptide by cell culture and a method for selecting an antigen-binding variable domain using the polypeptide. Besides, there are presented compositions and methods for using for the purpose of treating a malignant tumour and conditions related to the immune system.

EFFECT: use of the invention can find application in medicine in treating and diagnosing the tumour diseases.

88 cl, 29 dwg, 1 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: what is presented is an antibody neutralising endothelial cell infection by human cytomegalovirus (hCMV) characterised by the presence of three heavy chain CDR and three light-chain CDR. There are described: a nucleic acid for antibody expression containing coding NA and a cell based on such expressing NA. There are disclosed: a composition for preventing and treating hCMV based on the antibody and the use of the antibody or NA for preparing a drug for treating hCMV. The invention provides the antibodies the concentration of which are required for 50% neutralisation of hCMV in endothelial cells makes 0.003 mcg/ml or less that can find further application in methods of screening, as well as in diagnosing and treating the hCMV-mediated diseases.

EFFECT: higher effectiveness of the use of the antibodies.

13 cl, 5 dwg, 2 tbl, 3 ex

Compounds // 2466139

FIELD: chemistry.

SUBSTANCE: present invention relates to immunology and biotechnology. Disclosed are: versions of an isolated molecule of a human IL-6 antibody, which contain VH and VL; nucleic acid which includes an antibody-coding nucleotide sequence; a cell for obtaining the antibody molecule which is transformed by said nucleic acid. Described is a method of obtaining the antibody by cell culturing, a composition and a method of obtaining a composition of the antibody molecule.

EFFECT: invention can be used in medicine for treating diseases associated with IL-6.

34 cl, 1 dwg, 11 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: there are offered: versions of alpha5beta1 class IgG2 antibodies of hybridomas deposited under access number in ATCC No. PTA-7421, No. PTA-7420; as well as a conjugate of the antibody and the therapeutic agent, and the marked antibody for diagnosing a disease related to alpha5beta1 expression. There are also disclosed: a coding nucleic acid; an expression vector; a recombinant cell; a method for producing the antibody; a method for detecting alpha5beta1 protein; an antibody-based pharmaceutical composition; versions for applying the antibody for treating pathological angiogenesis.

EFFECT: use of the invention provides the antibody affine to Kd 0,1 nM which can find application in treating pathology associated with angiogenesis.

37 cl, 16 dwg, 6 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: disclosed is an antibody or fragment thereof, which specifically binds to folate receptor-alpha (FRα), as well as a dimer of Fab' antibody fragments, a pharmaceutical composition and use of antibodies or fragment thereof to obtain a medicinal agent. A nucleic acid molecule which codes a light chain antibody, an expression vector and a host cell are also disclosed.

EFFECT: use of the invention can find further use in treating and preventing disorders associated with FRα overexpression.

20 cl, 7 ex, 6 tbl, 13 dwg

FIELD: chemistry.

SUBSTANCE: disclosed is a nanobody against tumour necrosis factor-alpha (TNF-alpha) which has 4 framework regions FR and 3 HCDR. Described are versions of a nanobody-based polypeptide, each capable of binding with TNF-alpha. One version of such polypeptides contains at least one nanobody directed against human serum albumin. Corresponding coding nucleic acids are described. The invention also discloses a host cell for expression a nanobody and a host cell for expressing a polypeptide, each containing a corresponding nucleic acid; a method of producing a nanobody and a method of producing a nanobody-based polypeptide, where each of the methods employs the corresponding cell. Use of the nanobody to obtain a medicinal agent and a pharmaceutical composition against TNF-alpha are also discribed.

EFFECT: use of the invention provides a nanobody against TNF-alpha with high affinity, stability and suitability for production in multivalent format and low immunising power, which can be used in medicine to prevent, treat and diagnose TNF-alpha activity-mediated diseases.

80 cl, 62 dwg, 47 tbl, 65 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a binding protein which is specific to IL-13, having 6CDR sections (three light and three heavy chains). The invention discloses a structure of an antibody based on this protein and a conjugate based on the antibody. The invention describes versions of nucleic acid which codes the antibody or structure, and an expression vector, a replication vector and cells bearing such vectors. Described is a method of producing the protein by culturing cells and proteins obtained using said method. Described are compositions based on versions of the proteins.

EFFECT: invention can be used in medicine to treat and diagnose diseases associated with IL-13 activity which negatively affects health.

50 cl, 23 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to immunology and biotechnology. Claimed is isolated monoclonal antibody, inducing cytotoxicity with respect to cancer cells, produced by hybridome, deposited in collection ID AC under number 051206-01, or its antigen-binding fragment. Described are: chimeric and hymanised versions, obtained from said antibody. Described is hybridome, producing monoclonal antibody and deposited in collection ID AC under number 051206-01, as well as composition based on said antibody for treatment of human cancer tumour.

EFFECT: application of invention ensures versions of monoclonal antibodies capable of inducing cytotoxicity in vitro in the absence of effector cells with respect to lung adenocarcenoma cells, which can be applied in tumour therapy.

5 cl, 5 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a nanobody against tumour necrosis factor-alpha (TNF-alpha) which has 4 framework regions FR and 3 HCDR. Described are versions of a nanobody-based polypeptide, each capable of binding with TNF-alpha. One version of such polypeptides contains at least one nanobody directed against human serum albumin. Corresponding coding nucleic acids are described. The invention also discloses a host cell for expression a nanobody and a host cell for expressing a polypeptide, each containing a corresponding nucleic acid; a method of producing a nanobody and a method of producing a nanobody-based polypeptide, where each of the methods employs the corresponding cell. Use of the nanobody to obtain a medicinal agent and a pharmaceutical composition against TNF-alpha are also discribed.

EFFECT: use of the invention provides a nanobody against TNF-alpha with high affinity, stability and suitability for production in multivalent format and low immunising power, which can be used in medicine to prevent, treat and diagnose TNF-alpha activity-mediated diseases.

80 cl, 62 dwg, 47 tbl, 65 ex

FIELD: medicine.

SUBSTANCE: what is presented is an antibody characterised by the fact that it binds the human p40 IL-12 subunit and comprises six CDR regions (CDR1, CDR2, CDR3 from the light chain and CDR1, CDR2, CDR3 from heavy chain). There are described: an antibody construct, an antibody conjugate, versions of coding nucleic acid, versions of vectors (for expression and replication), versions of a host cell, a method for producing the antibody, versions of compositions, versions of a method of treating an individual having unfavourable IL-12 activity, a method of reducing IL-12 activity in a human.

EFFECT: use of the invention can find application in medicine for prevention and treatment of acute and chronic diseases associated with activity of the human p40 subunit.

115 cl, 24 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: there are presented versions of a humanised monoclonal antibody to hepatocyte growth factor. What is described is a cell line producing the antibody. There are offered a pharmaceutical composition and a method of treating tumours on the basis of the antibody, as well as using the antibody for producing a drug for treating a malignant growth.

EFFECT: new neutralising antibody to hepatocyte growth factor that can find application in treating cancer in an individual.

8 cl, 8 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: present invention refers to immunology. What is contemplated is an antibody which specifically binds sphingosine-1-phosphate (S1P), and its antigen-binding fragment. There are presented a pharmaceutical composition, an antibody expression vector, a host cell, as well as a method of treating an S1P-related disease or disorder.

EFFECT: use of the invention can find further application in treating various S1P-related diseases.

17 cl, 26 ex, 11 tbl, 13 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to immunology and biotechnology. There are offered versions of a TNF-alpha polypeptide wherein a number of heavy-chain single domain antibodies is equal to two. What is described is coding nucleic acid. There are disclosed versions of the compositions, a polypeptide-based kit, as well as versions of using it. What is described is a method for producing the polypeptide with using nucleic acid.

EFFECT: use of the invention provides the substantial growth of cytotoxicity lC50 (of the order of 10-9) that can find further application in therapy of TNFα-mediated disorders.

52 cl, 18 dwg, 11 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to auristatin peptides, including MeVal-Val-Dil-Dap-norephedrine (MMAE) and MeVal-Val-Dil-Dap-Phe (MMAF), and these peptides were attached to ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting "ligand-drug" conjugates are active in vitro and in vivo.

EFFECT: high activity of the compounds.

118 cl, 19 dwg, 12 tbl, 33 ex

FIELD: medicine.

SUBSTANCE: what is described is a method for malignant cell elimination with the use of an effective amount of an immunotoxin with a common structure, containing a core unit of gelonin toxin and a one-chained antibody specifically targeted on a malignant cell. According to the invention, the immunotoxin can be an ingredient of a pharmaceutically acceptable composition. The immunotoxin can be delivered to the malignant cell by introduction into a cell of an immunotoxin-expressing construct which is a viral vector.

EFFECT: immunotoxins according to the invention exhibit lower antigenic specificity with preserved biological activity, therefore the method and the composition used in the method have substantial positive properties for a subject requiring such method.

12 cl, 11 dwg, 9 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to immunology and biotechnology. What is offered is a TAT 10772 antibody which is characterised by the presence of six CDR. What is described is a method for identifying the antibody which binds TAT 10772 polypeptide. What is disclosed is using the antibody according to claim 1 for TAT 10772 expressing cell growth inhibition, and for therapeutic treatment of a tumour in a mammal where the tumour expresses TAT 10772. There are described: a presence-absence test of TAT 10772 protein in a sample which is supposed to contain it, and a method of diagnostic detection of a TAT 10772 expressing tumour, based on using the antibody according to claim 1.

EFFECT: presented inventions can find further application in therapy and diagnostics of TAT 10772 expressing tumours.

31 cl, 37 dwg, 11 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention discloses an isolated antibody which selectively binds to the C-end of beta-amyloid (Abeta) and is humanised or fully human. The antibody can be a single-chain antibody (scFv), a Fab fragment or a P(ab')2 fragment. The antibody is capable of preventing oligomerisation of Abeta. The invention discloses a nucleic acid sequence which codes the disclosed antibody, a vector and a host cell for producing the antibody, as well as a pharmacological composition for treating neurological disorders, particularly Alzheimer's disease. The invention provides methods for diagnosis using labelled antibodies disclosed herein and treating neurological disorders associated with abnormal accumulation and/or deposition of Abeta in the central nervous system by administering a therapeutically effective amount of a polynucleotide, vector or host cell to a subject.

EFFECT: invention enables successful application of the disclosed antibodies for therapeutic purposes and clinical application since in contrast to mouse antibodies, said antibodies are low- or nonimmunogenic when used in humans.

25 cl, 23 dwg, 1 tbl, 17 ex

Up!