靶向癌症治疗试剂_抗体_药物偶联物_英文_

Antibody-drug conjugates as targeted cancer therapeutics

SUN Yu1, 2*, YU Fei1, SUN Bai-wang1

(1. School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China;

2. School of Pharmacy, Jiangsu University, Zhenjiang 212013, China)

Abstract: Traditional chemotherapy has become one of the essential treatments of cancer. However, cytotoxic agents are not tumor specific, which would cause serious side effects. Antibody-drug conjugates (ADCs), also called immunoconjugates, belong to the “targeted chemotherapeutics” category of anti-cancer drugs. ADCs are composed of three components including the cytotoxic drug, the monoclonal antibody, and the linker connecting the drug to the antibody. With the special-binding between antibody and antigen expressed on the surface of targeted cancer cells, ADCs provide a method to achieve excellent localization of the drug at the desired site in the body. The internalization and formation of ADCs are crucial in designing and applying an antibody conjugate to a particular disease model. In this review, we summarize three distinct internalization routes of ADCs and analysis the structure of ADCs. We also discuss in detail the categories and interaction of every component, as well as their influence to targeting property, liability and activity.

Key words: antibody-drug conjugate; targeted cancer therapeutics; internalization; component CLC number: R916 Document code: A Article ID: 0513-4870 (2009) 09-0943-10

靶向癌症治疗试剂——抗体-药物偶联物

孙 玉1, 2*, 于 菲1, 孙柏旺1

(1. 东南大学化学化工学院, 江苏 南京 211189; 2. 江苏大学药学院, 江苏 镇江 212013)

摘要: 化疗已经成为癌症治疗的一个必要手段。然而, 细胞毒性试剂对肿瘤细胞缺少特异性, 导致严重的副反应。抗体-药物偶联物 (ADCs), 也被称为免疫偶联物, 属于靶向抗癌药物的一种。抗体-药物偶联物由药物、抗体以及偶联抗体和药物的连接键三部分组成。当抗体和癌细胞表面的抗原特异性结合时, 抗体-药物偶联物即可将药物成功靶向体内部位。抗体-药物偶联物的内在化过程和组成部分在设计和应用抗体偶联物到广泛的疾病模型中至关重要。本文概述了抗体-药物偶联物内在化的三个途径, 并对它们的结构进行了分析, 详细讨论了各个组成部分的类型、相互作用及其对抗体-药物偶联物的靶向性、稳定性和活性的影响。

关键词: 抗体-药物偶联物; 靶向癌症治疗; 内在化; 构成

Chemotherapy is an integral to current cancer therapy,

because it is effective in many cancers, such as acute childhood leukemia and Hodgkin disease. However, systemic administration of chemotherapeutic drugs not only results in the death of cancer cells, but also has the undesired side effects of destroying oral and intestinal mucosa, hair follicles, and bone marrow.

Received 2009-01-05. *

Corresponding author Tel / Fax: 86-25-52090614,

E-mail: whsunyu@163.com

Much attention has been directed to selective targeting of these agents by conjugation to antibodies against tumor specific markers, so as to improve efficacy and reduce side effects[1, 2]. Antibody-drug conjugates (ADCs), also called immunoconjugates, belong to the “targeted chemotherapeutics” category of anti-cancer drugs. They are composed of one or several cytotoxic drug molecules covalently linked to a monoclonal antibody binding to an antigen expressed on the surface of targeted cancer cells. The linkers within these

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internalization of ADCs should be compared to their conjugates are often designed to be cleaved through

respective antibodies. Some ADCs were found to changes in pH, reduction, or by proteases so that the

drug can be preferentially released at the tumor site. internalize with rates similar to those of their respective As a result, ADCs can increase the effective drug antibodies, such as conjugates of an anti-CD30 antibody

with auristatin[7]. However it was reported that some concentration within the targeted area, thereby optimize

the therapeutic effect of the agent. In addition, with ADCs were internalized more efficiently than the targeted delivery, the clinician may be able to lower the respective antibodies. These ADCs include the mAbs dose of the therapeutic agent which is particularly c1F6 (or cAC10) doxorubicin derivatives conjugates[8], necessary if the drug payload has associated toxicities or the anti-melanotransferrin antibody (or anti-CD20) if it is to be used in the treatment of chronic conditions. auristatin conjugates[9], the anti-CD79b auristatin F

The concept of arming antibodies by conjugation derivatives conjugates[10] and so on. to protein toxins dated back to 1970[3], and was followed The internalization of ADCs are desirable and

often indispensable for efficient drug release, depending by antibody conjugates with cytotoxic drugs a few

on the drugs and linkers. Because antibodies cannot years later. Antibody therapeutics have come of age

penetrate cellular membranes, they can only get inside in the intervening decades with the advent of hybridoma

mammalian cells via three distinct internalization routes: technology to develop murine monoclonal antibodies

clathrin-mediated endocytosis, caveolae-mediated uptake, (MAb), chimerization and humanization to address the

and pinocytosis. The first two types of antibody uptake shortcomings of murine MAb as therapeutics, and more

are antigen-mediated, while the last one is antigen- recently with direct routes to human antibodies using

independent. The antigen-mediated pathways normally phage display or transgenic mice. The clinical potential

result in accumulation of ADCs on the plasma membrane of ADCs has been greatly enhanced by improved

choices of targets, conjugated more potent drugs to at a local concentration higher than that of the

surrounding medium, particularly if the antibody has a improve stability and greatly expanded knowledge of

high affinity. On the other hand, pinocytosis occurs ADC cell biology and pharmacology.

through sequestration of liquid which contains the ADC Numerous preclinical efficacy studies illustrate

that ADCs have significant potential for enhancing the at the concentration added to the medium. As a result, antitumor activity of “naked” antibodies and reducing to achieve equal rates of internalization, a higher

[4,5]

the systemic toxicity of the conjugated drugs. concentration of the ADC in the medium would be Furthermore, the FDA has granted approval for the needed to deliver the same amount of conjugate via first antibody drug conjugate for human therapeutic pinocytosis inside the cell than via an antigen-mediated use in 2000. This conjugate (gemtuzumab ozogamicin pathway. (Mylotarg®)) consists of a humanized anti-CD33 mAb The molecular mechanism of clathrin-mediated linked to the cytotoxic antibiotic ozogamicin (N-acetyl- endocytosis (Figure 1) can be characterized as follows[11]: γ calicheamicin). It was licensed for the treatment of To regain their cytotoxic activity, the cytotoxic agent acute myeloid leukemia (AML) in patients over sixty has to be cleaved from the chemo-immunoconjugate. years of age and deemed unsuitable for cytotoxic Uptake of antibodies predominantly occurs via the chemotherapy[6]. clathrin-mediated endocytosis pathway. After binding 1 Internalization of ADCs the respective antigen associated with coated pits,

The therapeutic concept of ADCs is to use an antibody-drug conjugates will be readily endocytosed, antibody as a vehicle to deliver a cytotoxic drug to a from where they transit through several stages of tumor cell by means of binding to the antigen on transport and endosomal vesicles and finally end up in a targeted cell surface. ADCs are commonly in IgG lysosome. There, linkers and antibody will be cleaved format with 2–8 drugs/antibody. After internalization releasing the cytotoxic agent which-after exit from the into the targeted cell, ADCs can release drugs for lysosomal compartment-exerts its cytotoxic effect. activation. For some antibodies and its ADCs, clathrin-mediated

The major factor that contributes to the selective endocytosis is a major route for the intracellular uptake. cytotoxicity of ADCs is the conjugated antibody It is reported that the cytotoxic activity of an anti-CD70 that targets tumor-associated antigen, so the rates of antibody and its auristatin conjugates was associated

SUN Yu, et al: Antibody-drug conjugates as targeted cancer therapeutics

· 945 · with their internalization and subcellular trafficking through the endosomal-lysosomal pathway[12]. Also, the intracellular uptake of several auristatin conjugates of anti-CD30 mAb cAC10 and of trastuzumab is blocked by inhibitors of clathrin-mediated endocytosis, but not by inhibitors of caveolae-mediated uptake. Thus these ADCs do not alter the fate of antibody- antigen complexes[11,13]. But the conjugation of anti- CD20 antibody and auristatin internalize via both clathrin-mediated endocytosis and the caveolin-mediated uptake, as indicated by co-localization of this conjugate with clathrin and caveolin[14]. While at high concen-trations, ADCs may kill cells in an antigen-independent manner. Through examining the non-specific killing by gemtuzumab ozogamicin, the authors concluded that the cytotoxicity was derived from the ability of cells to take up conjugate dissolved in the surrounding medium via pinocytosis[15]. However, an accurate quantification of the amount of pinocytosed ADCs at various concen-trations has not been reported.

high thiol concentrations in the cytosol, and proteolytic enzymes in lysosomes. Thus, when designing and applying an antibody conjugate to a particular disease model, we need to address the basic conditions of drugs, antibodies and linkers used in ADCs. 2.1 Cytotoxic drugs used in ADCs

The choice of drug payload is critical because it would affect desired efficacy towards the targeted disease and its stoichiometry, orientation, or associated chemistry of conjugation to the antibody would hinder biological activity of the antibody. Up to now, about six categories of highly cytotoxic drugs have been con-jugated to monoclonal antibodies: anthracycline drugs, CC-1065 analogs and duoearmycin analogs, taxoids derivatives, calicheamicin derivatives, maytansinoids, dolastatin derivatives. Early ADCs exploited conven-tional anti-cancer drugs (e.g. doxorubicinand[16], tax-ane[17]) because of their ready availability, amenability to chemical manipulation and their well known toxico-logical properties. But these ADCs were moderately potent and usually less cytotoxic for the targeted tumor cells than the corresponding unconjugated drugs. Nowadays, many novel ADCs focus on such highly potent drugs as calicheamicins, maytansinoids and auristatins. Because new cytotoxic agents possess the following properties[18]: ① high potency in vitro toward tumor cell lines, with IC50 values in the range of 0.01–0.1 nmol·L–1 (i.e., active in the concentration range of antibody binding to tumor cells); ② a suitable

Figure 1 Internalization of antibody-drug conjugates

2 Considerations in design of effective ADCs

Effective delivery to the targeted cells is a prereq-uisite for high efficacy and low toxicity of any drug substance. Conjugation of a drug to an antibody provides a method to achieve excellent localization of the drug at the desired site in the body. Many kinds of antibodies, drugs, and linkers have been combined to prepare ADCs. Cytotoxic drugs used in ADCs generally have potencies several orders of magnitude greater than for conventional chemotherapeutics, making them too potent for systemic delivery. Linkers used to attach the drugs to the antibody delivery vehicles have been designed to exploit intracellular conditions for drug release including the acidic environment of endosomes (pH 5.5–6.2) and lysosomes (pH 4.5–5.0),

functional group for linkage to an antibody (if a functional group is not already present, the desired substituent has to be introduced at a suitable site to retain potency of the parent drug); ③ reasonable solubility in aqueous solutions to enable the reaction with antibodies, and ④ prolonged stability in aqueous formulations commonly used for antibodies.

The following three tables list the components and applications in cancer therapy of some representative ADCs (antibody calicheamicin conjugates, antibody maytansinoid conjugates, antibody auristatin conjugates). The particular properties and the internalization routes will be further elaborated in the following parts. 2.2 Antibody engineering contribute to ADCs

Antibodies are extremely versatile targeting proteins. Molecular engineering has been used to modify the size and pharmacokenetic properties of antibodies, alter the valency of antigen binding, and even alter effector activity. The main purpose of this

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Table 1 Antibody calicheamicin conjugates

Conjugate name

Drug

Antibody P67.6, CMA676

Linker class Hydrazone linker,

amide linker

Mean Drug/ Antibody ratio

Cancer Reference

Anti-CD33 antibody CalichDMH, calicheamicin conjugates CalichDMA Anti-CD20 antibody CalichDMH, calicheamicin conjugates CalichDMA Anti-MUC1 antibody CalichDMH, calicheamicin conjugates CalichDMA

2–3 Acute myeloid leukemia 19

(AML) 2–3 non-Hodgkin’s B-cell

lymphoma

Breast and ovarian tumor B-lymphoma malignancies Cancer cells with highly expressed Lewisy

13 20 21 22

Rituximab AcBut linker,

amide linker

hCTM01 Hydrazone linker, 2–3

amide linker

AcBut linker AcBut linker

5–7 2, 3

Anti-CD22 antibody CalichDMH CMC-544

calicheamicin conjugates Anti-Lewisy antibody CalichDMH calicheamicin conjugates

hu3S193

CalichDMH: N-acetyl γ calicheamicin dimethylhydrazide; CalichDMA: N-acetyl γ calicheamicin dimethyl acid; AcBut linker: an acid-labile 4-(4’-acetylphenoxy) butanoic acid linker including a hydrazone linker and a disulfide linker

Table 2 Antibody maytansinoid conjugates

Conjugate name

Drug

Antibody huC242

Linker class Disulfide linker

Mean Drug/

Antibody ratio

3–4

Cancer Reference

Cancer with CanAg antigen

23 24 25

huC242 Antibody DM1, DM4 maytansinoid conjugates

Anti-CD138+ antibody DM1 B-B4 Disulfide linker 3.5 CD138+ Multiple myeloma maytansinoid conjugates cells Anti-CD56 antibody maytansinoid conjugate

DM1 huN901 Disulfide linke 3–4 CD56+ Multiple myeloma

cells

DM1: N2'-deacetyl-N2'-(3-mercapto-1-oxopentyl)-maytansine; DM4: N2'-deacetyl-N2'-(4-mercapto-4-methyl-1-oxopropyl)-maytansine

Table 3 Antibody auristatin conjugates

Conjugate name

Drug

Antibody

Linker class

Mean Drug/ Antibody ratio

4, 8

Cancer Reference

26 27

CR011-vcMMAE MMAE CR011 Peptide linker Anti-CD70 auristatin conjugates Anti-CD79 auristatin conjugates Anti-CD30 auristatin conjugates

MMAF, AFP

m1F6, c1F6

Peptide linker

2.7 Melanoma

Renal cell carcinoma

MMAF CD79a, CD79b Maleimidocaproyl NA non-Hodgkin lymphoma 10

linker (NHL) MMAE,

MMAF

cAc10 Hydrazone linker, 2, 4, 8

dipeptides linkerTHIOMAB

Disulfide linker

2

CD30+ malignant cells Ovarian cancer

28 29

Anti-MUC16 THIOMAB MMAE auristatin conjugates

MMAE: monomethyl auristatin E; MMAF: monomethyl auristatin F; AFP: auristatin phenylalanine phenylenediamine; NA: not available; THIOMAB: engineered antibodies which are created by replacing Ala114 at the junction of the CH1 domain and the variable heavy chain domain with cysteine

stoichiometries (2 or 4 drugs/antibody) and sites of drug work is to produce new mAbs, mAb fragments, and

attachment. This strategy for generating antibody- mAb constructs that have both high tumor to non-tumor

binding ratios and high intratumoral localization drug conjugates with defined sites and stoichiometries

of drug loading didn’t change the antigen-binding characteristics. The research show that ADCs prepared

affinities, in vitro cytotoxic activities and in vivo with these Fab’ fragments demonstrate a more

properties[28]. A novel method was used to improve homogeneous affinity than any conjugates prepared

with the whole antibody[30, 31]. Another feasible engi-the therapeutic index of ADCs by engineering cysteine substitutions at positions on light and heavy chains neering approach was to replace the solvent-accessible

that provide reactive thiol groups. This THIOMAB cysteines forming the interchain disulfide bonds in

approach provided reactive thiol groups and did not cAC10 with serine, and in this way, to reduce the eight

perturb immunoglobulin folding and assembly, or alter potential conjugation sites down to 2 or 4. These

antigen binding[29]. So we can conclude that antibody Cys→Ser antibody variants were conjugated to MMAE

in near quantitative yield (89%–96%) with defined engineering will undoubtedly play an extremely

SUN Yu, et al: Antibody-drug conjugates as targeted cancer therapeutics

· 947 · important role in the new generation of gradually influence to drug release and internalization. developing drug conjugates. Until now functional 2.3.1 Hydrazone linker There are three general antibodies that are currently approved for the treatment methods for producing ADCs through hydrazone bond of cancer include Rituxan (rituximab) for B-cell formation. The first method is the aldehydes and lymphomas, Herceptin (trastuzumab) for breast cancer, ketones are generated through carbohydrate oxidation Campath (alemtuzumab) for certain leukemias, and of antibody by sodium periodate, and then hydrazones Erbitux (cetuximab), Vectibix (panitumumab), and are formed after addition of hydrazide drug derivatives Avastin (bevacizumab) for colorectal cancers. under acidic conditions. The advantage of this meth-odology is that mAbs are modified regiospecifically, 2.3 Linker category for conjugation

since the carbohydrates on mAbs are largely restricted The linker between the antibody and drug has to

to the Fc region. However, the oxidation methods are be designed in a manner that not only ensures stability

so complex that the resulting hydrazones are poorly during circulation in blood but allows the rapid release

of an active form of the cytotoxic drug inside the defined and the oxidative conditions can also lead to

methionine oxidation which will weaken the mAb targeted tumor cells. Furthermore, the conjugate must

remain intact during storage in aqueous solution to binding activity. Another alternative approach to

forming mAb-hydrazone linked conjugates is to attach allow formulations for convenient intravenous admini-stration. So, conjugation technology is a critical an aldehyde, ketone, or preformed hydrazone to the surface of mAb by acylation of lysine amino groups. aspect in generating effective ADCs and optimization

This approach allows much greater control over the strategies which are varied with the drug, linker, and

relative hydrolysis rates of the hydrazone bond. But the antibody used. Nowadays, there are largely three

today, the widely used method is conjugating a drug classes of linkers that used in ADCs: hydrazone linker,

hydrazide derivative with an antibody through a spacer disulfide linker and peptide linker. And the data of

(such as polymer and AcBut linker). research indicate that each type of drug might require

its own class of linker. The acid-labile hydrazone The antibody-targeted polymer-doxorubicin con-linker mainly exists in antibody-calicheamicin conjugate, jugate (Figure 2) is synthesized by conjugating Dox the optimal linker for maytansinoid-antibody conjugate with antibody via a HPMA hydrazone spacer which is is found to be a hindered disulfide moiety and the susceptible to pH-controlled hydrolysis. These con-optimal linker for auristatin-antibody conjugate appears jugates are relatively stable in blood (pH 7.4), but to be a peptide linker that is readily cleaved in release Dox and activate it under mild acidic conditions lysosomal compartments. The following discussion (pH 5) modeling endosomal and lysosomal environ-talks mainly about the characters of linkers and their ment inside the cells. Owing to the detailed structure

Figure 2 The antibody-targeted polymer-doxorubicin conjugates with pH-controlled activation. A: Classic HPMA-based conjugate; B: Hydrazone HPMA-based conjugate

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Figure 3 Structure of antibody-CalichDMH conjugate

of the polymer, the HPMA spacer and method of antibody conjugation, the cytotoxicity of the hydrazone conjugates is higher than that of classic conjugates[32].

Most antibody-CalichDMH conjugates (Figure 3) are synthesized by conjugating calicheamicin hydrazide derivative with antibody via an acid-labile 4-(4’-ace-tylphenoxy) butanoic acid (AcBut) linker[21,22] compris-ing a hydrazone and a sterically hindered disulfide. This optimized conjugate chosen for clinical trails is anti-CD33-calicheamicin, (gemtuzumab ozogamicin orMylotarg), which is the first ADCs approved for hu-man use and synthesized by this method. The cyto-toxic element in Mylotarg is N-acetyl-γ calicheamicin, and the mAb moiety is a humanized form of P67.6. The hydrazone cleavage and the disulfide reduction, which are caused by the acid conditions and high glu-tathione concentrations of the activated lysosomes, in-duce delayed release of the drug from its delivery antibody after endocytosis[33].

2.3.2 Disulfide linker Hindered disulfides play a significant role as linkers for ADCs. They have been used to link toxoids to antibodies against the epidermal growth factor receptor. For example, mAb-toxoid conjugates were prepared by a highly cytotoxic C-10 methyldisulfanylpropanoyl taxoid with mAbs KS-61 and KS-77 through a disulfide linker (Figure 4). Both of the above ADCs showed remarkable antitumor activity against human squamous cancer (A431) xeno-grafts in SCID mice, resulting in complete inhibition of tumor growth in all the treated animals without any systemic toxicity in the whole period of the experi-ment[16]. Disulfide-linkers also are optimal linkers for maytansinoid conjugates such as in huC242-DM4 (Figure 5)[23]. These disulfide linkers are stable in aqueous solutions, however, can be cleaved through

a disulfide exchange reaction. The rate of such exchange reactions can be controlled through the degree of hindrance on the proximal carbon atoms on the disulfide bond. The half-life in mice of maytansinoid conjugates is about 2−4.2 days.

2.3.3 Peptide linker The inherent instability of hydrazone and disulfide linkers has been the drive of studies towards the identification of peptide sequences that can be used to attach drugs to mAbs. Several dipeptides were found to be suitable for drug conjugation, based on indefinite stabilities in serum and neutral pH, and rapid cleavage by lysosomal extracts or purified

Figure 4 Structure of mAb-toxoid conjugate

Figure 5 Structure of maytansinoid conjugate

SUN Yu, et al: Antibody-drug conjugates as targeted cancer therapeutics

· 949 · cathepsin B. Because the proteases lead to mainly intracellular drug release, and are less active in the blood, this approach is particularly attractive. For example, by introducing a hydrophilic methoxy-triethylene glycol chain onto the doxorubicin portion of the branched peptide linkers (Figure 6), aggregation has been eliminated or greatly reduced in the immunocon-jugate products. The data suggested that the methoxy-triethylene glycol chain hydrolyzed as designed upon antigen-specific internalization into tumor lysosomes in vitro, where enzymatic degradation of the peptide linker released free doxorubicin[15].

The peptide linkers are the optimal linkers for auristatin conjugates, which are sensitive to lysosomal cathepsin B-catalysed hydrolysis. In cAC10-valine- citrulline-MMAE (Figure 7), a protease-sensitive dipeptide linker was designed to release MMAE by lysosomal cathepsin B in targeted cells but maintain a stable linkage and attenuate drug potency in circulation. Evaluation of ADC from mouse circulation showed the linker half-life to be about 144 hours, significantly greater than that reported for disulfide- or hydrazone- linked ADCs in mice or human trials[34].

Moreover, Doronina[35] analyzed the internalization of auristatin ADCs which are varied with the category and character of the linker. MMAE and AEVB conju-gates (Figure 8) were prepared by conjugating dolastatin 10 analogs auristatin E (AE) and monomethyl auristatin E (MMAE) with the chimeric mAbs cBR96 (specific to Lewis Y on carcinomas) and cAC10 (specific to CD30 on hematological malignancies). The linkers used for conjugation included an acid-labile hydrazone and

Figure 6 Structures of dox peptide linkers and BR96 conjugates

Figure 7 Structures of cAC10 ADCs and cathepsin B reaction products

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药学学报 Acta Pharmaceutica Sinica 2009, 44 (9): 943−952

Figure 8 Sturctures of potent monoclonal antibody auristatin conjugates. Drug is released from the peptide conjugates 1 and 2 through enzymatic hydrolysis (step a) and spontaneous fragmentation (step b) of the p-aminobenzylcarbamate intermediate. Drug is released from mAb-AEVB conjugates through hydrazone hydrolysis (step c) and hydrolysis of the ester (step d)

protease-sensitive dipeptides, leading to uniformly substituted conjugates that efficiently released active drug in the lysosomes of antigen-positive tumor cells. The peptide-linked mAb-valine-citrulline-MMAE and mAb-phenylalanine-lysine-MMAE conjugates were much more stable in buffers and plasma than the conjugates of mAb and the hydrazone of 5-benzoylvaleric acid-AE ester (AEVB). The mAb-Val-Cit-MMAE conjugates exhibited greater in vitro specificity and lower in vivo toxicity than corresponding hydrazone conjugates.

All theses ADCs illustrate the importance of the linker category, drug potency and conjugation method-ology in developing safe and efficacious mAb-drug conjugates for cancer therapy. 3 Conclusion and perspective

After more than 20 years of research, the ADCs become a new potent prodrug for targeted cancer treat-ments in clinics, and ADCs also show more superiority compared to standard anticancer agents. Especially with the approval of Mylotarg, ADCs have demonstrated a new level of clinical utility. But developing ADCs as a useful targeted therapeutic still faces several daunting challenges in practice: ① The recognization

between antibody and antigen that are expressed on the surface of cancer cells is indispensable and specific. But after conjugation the affinity of antibody and antigen may be weaken. To solve this problem engineered antibody should be widely designed and applied. ② Ideal release of drug should begin after the ADCs have entered the cancer cells to reduce the damage to the non-cancer issues. So specialized chemical linkages between the drug and the antibody that are only degraded intracellularly should be designed. ③ Recently, there are experts conclude that THIOMAB drug conjugates which are near-uniform, low-level conjugation of cytotoxins to antitumor antibodies can increase their tolerability without compromising anti- tumor efficacy[36]. This novel THIOMAB approach develops a new route of fabricating conjugations with high therapeutic index.

Thus we can forecast that further progress in the field of ADCs as targeted cancer therapeutics will appear by combining the advancements in drug and linker technologies with re-engineered mAbs that are designed to have optimal targeting properties.

SUN Yu, et al: Antibody-drug conjugates as targeted cancer therapeutics

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