Drug Module

Antibody-drug conjugates (ADCs) are next-generation targeted anti-tumor agents that are constructed by the covalent coupling of a monoclonal antibody with a cytotoxic payload drug via a small molecular linker. As a key factor in an ADC, the payload drug dictates its efficacy. At this moment, a large variety of payload drugs have been exploited in ADC and the number is on the rise. To facilitate the unique needs for different ADC development projects, Creative Biolabs has established an advanced “DrugLnk” organic synthesis platform with a large collection of payload drugs and linkers in the “drug module” and the “linker module”, respectively. Our scientists are highly experienced in full chemical synthesis, chemical modification, as well as bio-conjugation. We are dedicated to help our clients prepare innovated payload-linker complexes for novel ADC developments.

Drug Module

Properties of ADC Payloads

Toxic payload drugs are an essential component of any therapeutic ADC. In reality, not every toxin is suitable to be used as an ADC payload. To serve this very purpose, the toxins must meet some stringent criteria:

  1. The payload must exert extremely high cytotoxic efficacy (IC50 within the low pM to low nM range). Many factors, including IgG tumor penetration, target antigen expression level, ADC internalization… may lead to limited drug delivery and result in a low intracellular toxin level. Thus, high toxicity is needed to compensate the low drug concentration for efficient tumor cell killing.
  2. Since current ADC strategies rely on the internalization of the toxin conjugates to achieve drug delivery and the antibody and/or linker lysosomal degradation to achieve drug release, the targets of the payloads must be located inside the cell.
  3. A suitable payload should be small in size to minimize the risk of immunogenicity. It should also have decent water solubility to facilitate the aqueous conjugation reactions.
  4. An ADC payload should exert adequate plasma stability to maintain drug efficacy before reaching the target.

Based on these criteria, many payloads have been identified and developed into ADCs and their major intracellular targets include: microtubule, DNA, as well as DNA transcription machineries.

Microtubule Toxins

Microtubule toxins are a successful group of anticancer drugs that inhibit tumor cell growth and promote apoptosis by disrupting the assembly and dynamics of microtubules. They are generally applied in combination with other treatments against malignancies. In the form of an ADC, serious adverse effects of these microtubule toxins are greatly reduced, allowing the usage of these extremely potent agents for therapeutic applications. Creative Biolabs offers a variety of microtubule toxins, including maytansinoids, auristatins, epothilone, taxoids, tubulysins, and vinorelbine, as ADC payloads with suitable linkers and conjugation strategies.

Microtubule dynamic disruption by paclitaxel (right), a microtubule toxins that can be used in ADC development, comparing to control cells (left) (Nat. Prod. Rep.,2014). Microtubule dynamic disruption by paclitaxel (right), a microtubule toxins that can be used in ADC development, comparing to control cells (left) (Nat. Prod. Rep., 2014).

DNA Toxins

DNA toxins induce DNA damage and subsequently cell death by various mechanisms, such as double stranded DNA cleavage, DNA cross-linking… They are highly toxic agents with in vitro potency down to the picomolar level against tumor cell lines. With optimized linkers and conjugation strategies, DNA toxins are incorporated into ADCs for accurate drug delivery and an expanded therapeutic window. Creative Biolabs provides customized ADC preparation services using these DNA toxins, including duocarmycins and analogs, calicheamicins, PBD-dimers, doxorubicin, topotecan,bleomycin A2, dactinomycin, and mitomycin C.

Doxorubicin induced cleavage of double stranded DNA in different cancer cell lines (<em>Cancer Res.</em>, <strong>2006</strong>). Doxorubicin induced cleavage of double stranded DNA in different cancer cell lines (Cancer Res., 2006).

Transcription Toxins

Toxins targeting the DNA transcription machineries have been demonstrated as good candidates for ADC development. Currently, toxins against RNA polymerase II (the initial step in DNA transcription) and spliceosome (for correct mRNA maturation and processing) are being actively exploited. With extensive experience in synthetic chemistry and bio-conjugation, Creative Biolabs provides transcription toxins such as amatoxins (targeting RNA polymerase II) and thailanstatin A (targeting spliceosome) as ADC payloads.

 Amatoxin interaction with RNA-polymerase II. Overall crystal structure of α-amanitin with RNA polymerase II (left) and the amplified view of RNA polymerase II interaction with nucleic acids (middle) and α-amanitin (right) (Nat. Struct. Mol. Biol., 2008). Amatoxin interaction with RNA-polymerase II. Overall crystal structure of α-amanitin with RNA polymerase II (left) and the amplified view of RNA polymerase II interaction with nucleic acids (middle) and α-amanitin (right) (Nat. Struct. Mol. Biol., 2008).

Inhibitors

Various small molecule inhibitors, bearing unique chemical and cytotoxicity profiles, have also been exploited as ADC payloads. The process inhibited include oxidative phosphorylation (oligomycins), ATP biosynthesis (ipatasertib), and other important enzymes such as dihydrofolate reductase (DHFR, methotrexate) …

Other Payloads

With the development of fusion protein expression technology and nanoscience, the warfare against cancer has expended exponentially and many novel payloads based on these technological platforms, such as Nano-carriers, protein toxins, and toxic proteins for antibody-directed enzyme prodrug therapy (ADEPT), have also been exploited for ADC development.

With our well-established “DrugLnk” organic synthesis platform, the experienced scientists here at Creative Biolabs is dedicated to help you prepare various customized payload-linker complexes using toxins in the Drug Module for ADC development in a timely and cost-effective manner. Our customarily tailored services and high quality toxin products will contribute greatly to the success of your projects. In the meantime, we also provide other services for the benefit of ADC development. Moreover, Creative Biolabs also provides a variety of ADC toxin products and Drug-linker complex products. Please feel free to contact us for more information and a detailed quote.

References:

  1. Wang, X.; et al. In vitro and in vivo responses of advanced prostate tumors to PSMA ADC, an auristatin-conjugated antibody to prostate-specific membrane antigen. Mol. Cancer. Ther. 2011, 10(9): 1728-1739.
  2. Yu, S.F.; et al. A novel anti-CD22 anthracycline-based antibody–drug conjugate (ADC) that overcomes resistance to auristatin-based ADCs. Clin. Cancer. Res. 2015, 21(14): 3298-3306.
  3. Rohena, C.C.; Mooberry, S.L. Recent progress with microtubule stabilizers: new compounds, binding modes and cellular activities. Nat. Prod. Rep. 2014, 31: 335-355.
  4. Swift, P.L.; et al. Doxorubicin-DNA adducts induce a non-topoisomerase II–mediated form of cell death. Cancer Res. 2006, 66(9): 4863-4871.
  5. Brueckner, F.L.; Cramer, P. Structural basis of transcription inhibition by α-amanitin and implications for RNA polymerase II translocation. Nat. Struct. Mol. Biol. 2008, 15(8): 811-818.

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