Peptide-Conjugate Drug (PDC)

Targeted therapies that selectively bind and act through molecules expressed on the surface of cancer cells represent a major advance in cancer treatment because they are more effective and better tolerated than traditional cytotoxic drugs.

Three targeted approaches are implemented in cancer therapy to improve the specificity and antitumor efficacy of cancer treatments. Targeted agents, such as receptors or enzymes, can be developed to block proteins produced by tumor cells. Another strategy is to allow effector molecules (e.g., Adc, bispecific antibodies, or CAR-T) to attach to molecules overexpressed on the surface of tumor cells and suppress tumor cell proliferation synergistically while delivering a cytotoxic payload or triggering a tumor-directed immune response. The third strategy is to utilize peptide-conjugate drugs (PDCs), which promote the accumulation of toxic payloads in tumor cells.

Monoclonal antibodies are the basis for many of the targeted therapeutics now in clinical use, such as ADC. However, a range of physicochemical and pharmacological characteristics of ADCs limit their therapeutic applicability. Peptides employed by PDCs as tumor targeting carriers offer several benefits over ADCs, including ease of synthesis and the ability to rapidly add structural alterations to promote rational drug design for enhanced bioavailability, affinity, and stability. Furthermore, peptides are less immunogenic.

Structure of Conjugates

Conjugates developed for targeted delivery typically consist of three components, all of which contribute to the overall biological efficacy and selectivity of the drug. The carrier component is included in the structure, which targets tumor-specific markers. In addition to peptides, a range of other small molecules and biologics such as natural proteins, antibodies, mucoadhesives, designed anchor protein repeats, and aptamers have been investigated to provide tumor selectivity.

Carrier molecules are linked to active anticancer drugs and can induce a variety of biological functions. Currently, the toxins used for cancer therapy include cytotoxic molecules and radionuclides that mediate cytotoxicity. The covalent linker that connects the targeting carrier molecule to the effector molecule can be cleavable or non-cleavable. Once the coupled drug binds to the tumor cell and enters the tumor cell, the cleavable linker is able to control the drug release from the payload. The choice of cleavable or non-cleavable linker depends on the design of the targeted therapy and the requirements of the mechanism of action.

PDC

PDC has a similar structure to ADC but uses a peptide fraction to preferentially target drug couples to tumor cells and limit non-targeted cytotoxicity by releasing a cytotoxic payload at the tumor site or within the tumor.

There are several advantages of employing peptides as drug conjugate carrier molecules. In comparison to ADCs, they are simpler to synthesize and deliver well-defined, cost-effective targeted therapeutics. To increase bioavailability, binding affinity, and stability, structural modifications can be easily implemented to facilitate rational drug design. The incorporation of lipids/fatty acids increases peptide lipophilicity, allowing for the modulation of half-life and bioavailability via altering tumor penetration and cellular absorption. Peptides are also useful for combinatorial drug development, allowing for in vitro high-throughput screening of candidate structures to select peptides with the best pharmacodynamic characteristics. Peptides also have low inherent immunogenicity.

Cell-penetrating peptides (CPPs) and cell-targeting peptides (CTPs) are the two types of peptides employed in PDCs. PDCs with non-specific cell-penetrating homing peptides penetrate cells, whereas PDCs with cell-targeting peptides enter tumor cells by precisely attaching to antigens or receptors on the surface of tumor cells to mediate the cytotoxic payload. The poor cell specificity of CPPs limits the applicability of various types of PDCs. CTPs, on the other hand, have similar effects to monoclonal antibodies while overcoming some of their drawbacks, and are thus commonly utilized.

Only two PDCs are currently approved by the FDA for clinical cancer treatment: Melflufen and 177Lu-dotatate.

Melflufen is a highly lipophilic PDC that rapidly and passively crosses cell membranes. Once inside the tumor cell, the aminopeptidase-binding domain of Melflufen is acted upon by aminopeptidases and esterases and releases a payload of alkylating agents.177Lu-dotatate is a form of radiation therapy targeting that combines growth inhibitor analogs and radionuclides, linked by the chelator DOTA. Growth inhibitor receptors are expressed in more than 80% of highly differentiated neuroendocrine tumors, which provide an ideal target for PDC using growth inhibitor analogs as homing peptides.

A fan of biotechnology who likes to post articles in relevant fields regularly