WO1992014758A1 - Molecules conjuguees - Google Patents

Molecules conjuguees Download PDF

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Publication number
WO1992014758A1
WO1992014758A1 PCT/AU1992/000047 AU9200047W WO9214758A1 WO 1992014758 A1 WO1992014758 A1 WO 1992014758A1 AU 9200047 W AU9200047 W AU 9200047W WO 9214758 A1 WO9214758 A1 WO 9214758A1
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Prior art keywords
conjugate
antibody
fudr
nucleoside
polypeptide
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PCT/AU1992/000047
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English (en)
Inventor
Geoffrey Pietersz
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The Austin Research Institute
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Publication of WO1992014758A1 publication Critical patent/WO1992014758A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid

Definitions

  • This invention relates to conjugate molecules, particularly conjugates between drug molecules and polypeptides, and methods involving the same.
  • Most cytotoxic drugs used clinically have little selective toxic effect on tumours and although extensive structural modification has resulted in analogues with improved antitumour activity, dose limiting toxic side effects are still a major problem.
  • cytotoxic agents to tumours by covalently linking them to monoclonal antibodies confers a degree of specificity not found with the drugs alone.
  • the conjugation of a drug to monoclonal antibodies usually results in some loss of both drug and antibody activity. This, in combination with the relatively inefficient uptake of drug antibody conjugates, as a result of limited tumour access, has prompted the use of more potent drugs where relatively small doses inhibit tumour growth.
  • 5-Fluorouracil is used in the treatment of carcinoma of the breast and intestine, but its use is limited by toxicity to bone marrow and intestinal epithelium. This drug is metabolized by several enzymes and transformed into toxic species which interfere with several metabolic pathways.
  • 5-FU enters the pyrimidine biosynthetic pathway at the orotic acid step, to form 5- fluorouridine diphosphate which can be incorporated into RNA.
  • 5-Fluorouridine diphosphate is transformed to 2'- deoxy-5-fluorouridinemonophosphate which inhibits thymidylate synthetase resulting in the inhibition of DNA synthesis.
  • 2-Deoxy-5-fluorouridine is a more potent derivative of 5-fluorouracil.
  • Other nucleoside drugs such as bromodeoxyuridine and azidothymidine, are widely used in the treatment of tumours and viral infection. The effectiveness of these drugs is also somewhat limited due to their toxicity.
  • nucleoside drug molecules usually results in some loss of both drug and antibody activity.
  • nucleoside drugs such as 2'-deoxy-5-fluorouridine (5- FUdr), which contains a sugar moiety (pentose), and a nitrogenous heterocyclic base.
  • pentose 2,3-deoxy-5-fluorouridine
  • nucleoside drugs such as 2'-deoxy-5-fluorouridine (5- FUdr)
  • pentose pentose
  • a nitrogenous heterocyclic base a sugar moiety
  • the sugar moiety is often oxidised in coupling reactions with antibodies, causing a loss in drug activity.
  • nucleoside-polypeptide conjugate wherein said polypeptide is selected from an antibody or fragment thereof, growth factor, hormone or biologically active peptide; characterised in that the nucleoside is coupled to said polypeptide through a 3' ester linkage. The coupling takes place via an active ester, giving an ester linkage at the 3' position of the nucleoside and an amide linkage with the polypeptide.
  • the precise chemical structure of the active ester employed in the conjugation is not of importance, and may be derived, from N- hydroxysuccinimide, N-hydroxysulphosuccinimide, 1- hydroxybenzotriazole, pentafluorophenol, nitrophenol, and other active esters as are well known in the art.
  • said conjugate is represented by the formula:
  • the nature of the group R is not essential to this invention as this group acts as a spacer between the ester and amide linkages of compounds of the formula I.
  • Hormones which may form part of the conjugates of this invention include calcitonin, thyrotropin, melanotropin, insulin, gonadotropin and relaxin. Growth factors may include EGF, TGF ⁇ and ⁇ , IGF and FGF.
  • Cytokines which may form part of the conjugates of this invention include colony stimulating factors (such as G- CSF and GM-CSF), interleukins and other cytokines as are well known in the art.
  • Nu is 5-FUdr or a derivative thereof, bromodeoxyuridine, lododeoxyuridine, bromovinyluridine, azidothymidine (AZT), or any other nucleoside drug as are well known in the art (Merck Index, 11th Edition, Merck & Co., Inc., 1989).
  • substitutional variants thereof wherein: i) The F substitution at position 5 on the nitrogenous base is substituted with I, Cl or Br; ii) one or more of the carbon groups of the sugar moiety or nitrogenous base are substituted with halogen (F, I, Br, Cl), hydroxy, C1-C3 lower alkyl or the like; and/or iii) one or more of the carbon atoms in the sugar moiety, and nitrogen and carbon atoms in the base moiety are replaced with different atoms selected from S, 0, N or C.
  • the group R as defined above may be straight or branched chain alkyl, aryl, or a heterocyclic group, and may be unsaturated, saturated, or contain one or more single or double bonds.
  • the alkyl chain may be optionally substituted with halogen (I, Br, Cl or F), hydroxy, cyano, phenyl, amino, carboxy, alkyl, alkoxy or other substituents as are well known in the art.
  • the alkyl chain may be interrupted with a heteroatom (such as 0, N, S or P) which may be optionally substituted with substituents as are well known in the art.
  • antibodies may be polyclonal or monoclonal tumour reactive antibodies. Monoclonal antibodies are preferred, particularly in the light of their high degree of antigen specificity.
  • antibodies includes fragments of antibodies containing an antigen binding site such as Fab, or F(ab')2 fragments, chimeric antibodies, humanized antibodies (derived from an animal antibody, such as a murine antibody, wherein human amino acid sequences replace animal sequences), Fv antibodies, single chain antigen binding proteins, Dab, or any antibody fragment or derivative capable of binding antigen.
  • Polypeptides are generally coupled to nucleoside drugs such as 5-FUdr through nucleophilic groups of amino acids, particularly the amino group of lysine.
  • Polypeptide conjugates in accordance with this invention generally comprise 1 or more FUdr molecule conjugated to each polypeptide.
  • conjugates may contain from 1 to 100 molecules of 5-FUdr per antibody molecule.
  • the antibody conjugates of this invention are capable of binding to selected targets, such as tumours, for example breast tumours or colon tumours, or virally infected cells. Any tissue or cell type expressing antigenic determinants reactive with the antibodies, which form part of the conjugate of this invention, may be selectively killed through action of the nucleotide/- nucleoside drug molecule.
  • nucleoside drugs conjugation of nucleoside drugs to hormones, growth factors and cytokines allows specific targeting to sites having receptors or affinity for these reagents.
  • nucleoside-polypeptide conjugates which comprises reacting an active ester of said nucleoside (linked through the 3' carbon) drug with a polypeptide.
  • 3' active ester is meant an ester with an easily displaceable (under nucleophilic attack) OR group, where R is as previously defined.
  • Active esters may, for example, be derived from N-hydroxysuccinimide, N- hydroxysulphosuccinimide, 1-hydroxybenzotriazole, pentafluorophenol, nitrophenol and the like.
  • the polypeptide couples to the active ester through nucleophilic groups such as the amino group of lysine.
  • Active esters of nucleoside drugs generally comprise the formula LCO-R-COO-Nu; wherein:
  • L is any leaving group, such as nitrophenol, N- hydroxysuccinimide, chloro, fluoro, hydroxysuccinimide, N-hydroxysulphosuccinimide, 1-hydroxybenzotriazole, pentafluorophenol, nitrophenol and the like; and R and Nu are as previously defined.
  • the reaction conditions between the activated ester and polypeptide, such as an antibody, are generally unimportant, and may for example, be carried out at temperatures between about 4°C an ambient temperature (such as 17-25°C), or higher temperatures as desired, although such temperatures are generally below about 60"C.
  • the active ester is generally in excess to enable multiple labelling of each polypeptide molecule.
  • said nucleoside drug is AZT or 5-FUdr, or a derivative thereof.
  • a method for the treatment of tumours or viral diseases which comprises administering to a subject in need of such treatment an effective amount of a conjugate as hereinbefore defined optionally in association with one or more pharmaceutically acceptable carriers or excipients.
  • the polypeptide portion of the conjugate would be selected to be reactive with tumour cells or virally infected cells.
  • Tumours which may be treated in accordance with this invention include lymphoma, Hodgkin's disease, leukemia, melanoma, endothelial carcinomas, adenocarcinomas, and cancers of the breast, lung, liver, pancreas, prostate, ovary, stomach, kidney, testes, head and neck.
  • Viral diseases i.e. cells infected with virus
  • HIV include HIV, herpes virus, hepatitis A-E virus, cytomegalovirus and papilloma virus.
  • the specificity provided by the polypeptide portion of the conjugates of this invention enables precise targeting of the nucleoside drug to its site of action. It is believed that the conjugates of this invention would be internalised into cells on binding to cellular receptors, and the nucleoside drug component liberated from the conjugate within the cell, such as in lysosomes. The nucleoside drug would then be free to act as a cytotoxic agent.
  • Antibodies or antigen binding fragments thereof which may be used in this invention include antibodies reactive with MUC 1-3, CEA, CD3, CD4, CD5, CD7, CD8, CDll, CD18, CD19, CD25, EGF receptor, and the transferrin receptor (which antibodies are described in the 4th International Workshop on Lymphocyte Antigens citation reguire ) .
  • a method for the treatment of autoimmune disease or tissue rejection associated with transplantation which comprises administering to a subject in need of such treatment an effective amount of a conjugate as hereinbefore defied optionally in association with one or more pharmaceutically acceptable carriers or excipients.
  • Autoimmune diseases which may be treated in accordance with this aspect of the invention include rheumatoid arthritis, SLE, biliary cirrhosis, chronic active hepatitis and the like.
  • conjugates of this invention are generally directed against lymphocytes as lymphocytes play a key role in tissue rejection.
  • a method for clearing bone marrow of tumour cells which comprises treating bone marrow removed from a patient with a conjugate as previously described so as to kill tumour cells.
  • This aspect of this invention is particularly relevant to cancer therapy where bone marrow is removed from a patient suffering from cancer and the patient treated with cytotoxic reagents, such as chemotherapeutic reagents and/or radiation treatment. Treatment of this type generally destroys a patient's bone marrow which is then supplemented with the removed bone marrow.
  • such bone marrow may contain resident tumour cells, which can be removed using the conjugates of this invention.
  • the conjugates of this invention would be targeted against tumour cells such as utilising antibodies directed to tumour cell antigens.
  • Conjugates may be administered to patients by any convenient mode of administration, such as subcutaneous, intramuscular, intratumour, or intravenous injection; intravenous drip; transdermal delivery system; orally, parenterally and the like.
  • an effective amount refers to the amount of conjugate of this invention which is effective to ameliorate or treat tumourogenic, viral or other disease. What constitutes an effective amount will depend upon the nature and site of the tumour or viral disease being treated, physiological status of the patient, and judgement of the prescribing physician. In general terms, an effective amount of conjugate will comprise from .001 micrograms to 10 grams. A preferred dosage range is between 1 ⁇ g/kg to 100 mg/kg body weight.
  • the conjugate of this invention may be in the form of a sterile injectable form; tabletted for oral or rectal administration; in the form of a syrup or other aqueous solution of suspension; or in the form of a cream for tropical administration.
  • the conjugate of this invention is generally combined with one or more pharmaceutically acceptable carriers or excipients, such as saline, glycerol, physiological buffers having a pKa around 7 to 8; magnesium stearate; and/or other well known excipients/carriers to give a pharmaceutically acceptable composition (see Remingtons Pharmaceutical Sciences, Osol. et al., 17th Edition, Mack Publishing Co., Eastern Pennsylvania, which is incorporated herein by reference).
  • compositions comprising the conjugates of this invention may contain protease inhibitors, and antibacterial agents. Dispersants may also be provided to prevent aggregation, as may albumin or other protein sources to guard against proteolysis.
  • active ester 2'-deoxy-5- fluoro-3'-O-succinoyluridine may be substituted with any other active ester of a nucleotide/nucleoside drug having anti-tumour/antiviral properties.
  • monoclonal antibodies may be clearly substituted with hormones, growth factors, or other polypeptides.
  • the succinyl active ester is exemplary of a wide range of ester groupings as defined herein.
  • monoclonal antibodies are particularly exemplified.
  • such antibodies may be substituted with polyclonal antibodies, human antibodies, humanised antibodies, or fragments of antibodies having antigen binding capacity.
  • Tumour cells mean IC50 mean IC50 m meeaann I iCL, ⁇ n FUdr-succ 5-FUdr-MOAb
  • Anti-Ly-2.1 (lgG 2a ) reactive with the murine Ly-2.1 antigen was isolated from murine ascites fluid.
  • DCC dicyclohexylcarbodiimide
  • 5-FUdr (1) had to be chemically modified for conjugation and this was done by the introduction of a carboxyl group by succinylation of 5-FUdr.
  • succinylation of 5-FUdr was necessary to protect one of the two available hydroxyl groups of (1) prior to succinylation.
  • succinylation of the 3'-hydroxyl group occurred and deprotection gave the 3'- isomer as the only product, with a yield of 45% after the 3 steps.
  • the carboxyl group was activated by forming an ester with N-hydroxysuccinimide for coupling with monoclonal antibody.
  • Conjugates were obtained with protein recoveries in excess of 70%, even when up to 40 residues of 5-FUdr were coupled to MoAb. This significant protein recovery may well be due to the high hydrophilicity of the 5-FUdr-succ (4) which prevents precipitation of the antibody due to a loss of charged amino groups on the antibody. Thus, highly conjugated antibodies were obtained.
  • the IC50 of the conjugate in terms of antibody concentration was 2.5x10""* mg/ml on day 1.
  • the IC50 of the conjugate after 24 hr incubation without serum was identical to the initial IC50. However, when the conjugate was incubated with serum the IC50 was increased to 4x10"* mg/ml. Therefore, in the presence of feotal calf serum the cytotoxicity of the conjugate was reduced 1.6 fold indicating a loss of some 5-FUdr residues.
  • Cell lines used for biological assay were the E3 variant of the Ly-2.1 +ve positive murine thymoma ITT(1)75NS, and the Ly-2.1 _ve BW5147 OU " cells (BW).
  • the cells were maintained in vitro in Dulbecco's modified Eagles medium supplemented with 10% heat-inactivated newborn calf serum (Flow Laboratories (CSL), Sydney, Australia), 2mM glutamine (Commonwealth Serum Laboratories, Sydney, Australia), lOO ⁇ g/ml streptomycin (Glaxo, Melbourne, Australia) and lOOlU/ml penicillin (CSL).
  • Antibody Activity of 5-FUdr-MoAb Conjugates The antibody activity of the immunoconjugates was quantitated by flow cytometry after cytotoxic assay (a) or (b). The binding of the conjugates to Ly-2.1 +ve ITT(1)75NS E3 (E3) cells was measured by fluorescence of the cells after incubating with immunoconjugate, washing and exposure to fluorescein labelled rabbit-anti-mouse-antibody. The concentration of the immunoconjugate giving 50% of maximum fluorescence was calculated and compared with unconjugated MoAb to give a relative activity of conjugated to non-conjugated antibody.
  • the antibody activity of conjugates were also measured using a competition assay.
  • the antibody activity of conjugate measured using the competition assay was similar to the activity measured using the direct binding assay.
  • 5-FUdr-succ-MoAb containing 11, 19 or 26 drug residues showed no significant variation of their IC50 values in a cytotoxicity assay based on the concentration of 5-FUdr-succ (4) and on average were 12 times less toxic than 5-FUdr (1) (Table 1).
  • cytotoxicity assay was carried out using both Ly-2.1+ve E 3 ce n s ancj Ly-2.1 ⁇ ve BW cells.
  • conjugates were exposed to antibody reactive (E3) and antibody non- reactive (BW) cells for 30 min and washed and then incubated for 24 h and pulsed with [ ⁇ H]-deoxyuridine.
  • the IC50 for the anti-Ly-2.1 conjugate on E3 was 7.1x20 " 8 M while the IC50 on BW was >5.01xlO" 7 M and indicates that 5-FUdr-anti-Ly-2.1 conjugates are selectively toxic to Ly-2.1 +ve cells.
  • ITT(1)75NS E3 or Colo 205 cells were injected s.c. into the abdominal wall of CBF1 or swiss nude mice, respectively.
  • Treatment i.p. or i.v.
  • palpable tumours 0.4cm 2 - 0.6cm 2
  • Liml899 tumour implants of 0.1cm 2 were transplanted s.c. into the right flank of nude mice.
  • Treatment was begun once tumours were established and growth was evident.
  • Daily measurements with a calliper square measuring along two perpendicular axes of the tumour were carried out and data recorded as mean tumour size (cm 2 ) ⁇ Standard Error (SE).
  • mice of the same age and sex were used within an experiment.
  • the three mouse models used within this study were; the E3 tumour growing in CBF j mice which is a congenic tumour model, and Colo 205 and Liml899 which are human tumours grown in nude mice.
  • mice Groups of 8 CBF-L mice injected s.c. with 5xl0 6 E3 cells, developed tumours 7 days after inoculation and were injected i.p. with increasing doses of 5-FUdr-succ conjugated to anti-Ly 2.1 (48 ⁇ g, 70 ⁇ g, 85 ⁇ g or 100 ⁇ g).
  • the highest dose administered, lOO ⁇ g conjugated 5-FUdr- succ showed marked tumour inhibition, where tumours were 15.0% of control tumours on day 15 and 100% survival of mice was seen within this group. However, minor weight loss and some diarrhoea was observed. 50% tumour inhibition, compared with control tumours, was produced by the lowest dose of conjugated 5-FUdr-succ (48 ⁇ g) administered, by day 15.
  • the immuno-conjugates are potent inhibitors of tumour growth.
  • 5-FUdr-succ in an unconjugated form produced no tumour inhibition at all.
  • Increased dosages of 5-FUdr-succ conjugates produced increased tumour inhibition with minor signs of systemic toxicity in the mice at the highest dose only. Few drugs or drug conjugates have shown such tumour inhibiting potential at such low quantities.
  • the 5-FUdr-succ- ⁇ TFR conjugate which is unreactive with the E3 thymoma showed 7.0% tumour inhibition, while the specific conjugate, 5-FUdr- succ- ⁇ Ly-2.1, showed 60% tumour inhibition thus demonstrating the specificity of 5-FUdr MoAb conjugates.
  • the free drug and MoAb mixture (with doses of each equivalent to the an.ti-Ly-2.1 conjugate) showed 25% tumour inhibition, yet free 5-FUdr-succ at these low doses has been shown to have no anti-tumour effect (data not shown).
  • the MoAb ⁇ Ly-2.1 is an IgG2a and may therefore be able to participate in ADCC to inhibit tumour growth. Previous experiments using this antibody have shown similar results.
  • Nude mice bearing the Liml899 tumour as a xenograft were injected i.p. 21 days after implantation of tumour pieces, with a total of 66 ⁇ g of 5-FUdr-succ conjugated to 1-1 MoAb (PBS was injected as a control).
  • the i.p. administration of FUdr-succ-Ly-2.1 conjugates reduced tumours by 53.3% compared with controls.
  • the individual tumour growth curves for control mice and conjugate receiving mice clearly demonstrated the in vivo efficacy of FUdr succ conjugates at doses as low as 66 ⁇ g against the Liml899 colon carcinoma.
  • Colo 205 5-FUdr resistant
  • Groups of 6 Swiss nude mice were injected s.c. with 5x10° Colo 205 cells. Seven days later i.p. treatment was initiated where mice received either (a) PBS, (b) 5FUdrsucc-250-30.6 (Colo 205 reactive) or (c) 5FUdrsucc-anti-Ly-2.1 (Colo 205 non- reactive), every third day.
  • Conjugate groups received four doses of 5FUdrsucc total does 122 ⁇ g, (Day 7 - 31 ⁇ g, Day 10 - 30 ⁇ g, Day 13 - 25 ⁇ g, Day 16 - 36 ⁇ g). No significant differences in tumour growth between the various groups was observed.

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Abstract

Conjugués de nucléoside-polypeptide, dans lesquels le polypeptide est sélectionné parmi un fragment de liaison à l'anticorps ou à l'antigène d'un anticorps, d'une hormone, d'un facteur de croissance ou d'un peptide à activité biologique, et qui se caractérisent par le fait que le nucléoside est couplé au polypeptide au moyen d'une liaison d'ester 3'. Lesdits conjugués de nucléoside-polypeptide sont utiles dans le traitement des tumeurs ou des maladies d'origine virale.
PCT/AU1992/000047 1991-02-13 1992-02-13 Molecules conjuguees WO1992014758A1 (fr)

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AUPK458591 1991-02-13

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3943485A (en) * 1984-03-12 1985-09-19 Molecular Diagnostics, Inc. Nucleic acid-protein conjugate
US4650675A (en) * 1983-08-18 1987-03-17 The Children's Medical Center Corporation Oligonucleotide conjugates
AU8265987A (en) * 1986-12-24 1988-06-30 Eli Lilly And Company Immunoglobulin conjugates
EP0310251A2 (fr) * 1987-09-04 1989-04-05 Molecular Devices Corporation Système pour détecter l'ADN
AU2600688A (en) * 1987-10-28 1989-05-23 Howard Florey Institute Of Experimental Physiology And Medicine Oligonucleotide-polyamide conjugates

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4650675A (en) * 1983-08-18 1987-03-17 The Children's Medical Center Corporation Oligonucleotide conjugates
AU3943485A (en) * 1984-03-12 1985-09-19 Molecular Diagnostics, Inc. Nucleic acid-protein conjugate
AU8265987A (en) * 1986-12-24 1988-06-30 Eli Lilly And Company Immunoglobulin conjugates
EP0310251A2 (fr) * 1987-09-04 1989-04-05 Molecular Devices Corporation Système pour détecter l'ADN
AU2600688A (en) * 1987-10-28 1989-05-23 Howard Florey Institute Of Experimental Physiology And Medicine Oligonucleotide-polyamide conjugates

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