Antibody-drug conjugates (ADCs) are an advanced biopharmaceutical drug modality with unparalleled potential in precision medicine and oncology. ADCs consist of antibody carriers to which cytotoxic payloads are attached via linkers and combine the potency of cytotoxic drugs with the specificity of antibodies to specifically target cancer cells. The growing importance and increasing value of ADCs are underscored by multi-billion dollar acquisitions and partnerships within the pharmaceutical industry, exemplified by Pfizer’s $43 billion acquisition of Seagen in 2023. About a dozen ADCs are already used for oncology treatment in the clinic, with more than 100 ADC moieties at different stages of clinical trials. Despite their transformative impact in precision oncology for cancer treatment, ADCs face challenges, including complex pharmacology, limited variety of payloads, and evolving cancer resistance. These limitations and associated challenges are nevertheless being addressed through ongoing research and exploration of new ADC targets, linkers, and payloads.

Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are advanced RNA drug modalities, offering targeted approaches to disease treatment by targeting disease-relevant mRNA molecules. These therapies can alter or halt the production of proteins involved in diseases. Their advantages include high target specify, potential for long-lasting therapeutic effects, streamlined chemical synthesis, and the ability to reduce the expression of any protein, including proteins deemed “undruggable”. These RNA-based therapeutics embody the principles of precision medicine, offering a therapeutics that can be tailored to individual’s genetic profile for the treatment of rare genetic disorders. While several FDA-approved ASO and siRNA therapies are already making a difference for patients in the clinic, challenges still remain to be addressed for these therapeutic modalities to become more broadly implemented and target a wider range of conditions.

Cell therapies, which utilize living cells as therapeutic agents, are an advanced drug modality that represents a groundbreaking approach in medicine to treat or prevent diseases. Stem cells offer unparalleled potential in the treatment of hematologic malignancies and in regenerative medicine, while the majority of FDA-approved cell therapies are based on modified immune cells like dendritic cells and T-cells for immunotherapy. Pioneering therapies like Provenge (for prostate cancer) and various CAR-T therapies (for lymphomas and myelomas) have revolutionized cancer treatment by modifying a patient's own immune cells to specifically target and eliminate cancer cells, marking significant milestones in personalized cancer therapy. Despite the transformative potential of this advanced drug modality, cell therapies face challenges particularly in safety. Issues like adverse immune responses, manufacturing complexity, and regulatory hurdles are nevertheless being addressed through continuous research and innovation.

Peptide and protein therapeutics have revolutionized medical treatment, from life-saving insulin to modern blockbuster weight-loss drugs like Ozempic and Wegovy. These biopharmaceuticals offer unique therapeutic advantages such as high specificity and complex and diverse mechanisms of action, ranging from enzyme replacement therapies to immunomodulatory drugs and hormones, contributing to their therapeutic success. Despite challenges like limited oral bioavailability and immunogenicity, advancements in peptide chemistry and protein engineering are continually expanding their therapeutic scope and range of medical indications. The application of peptide and protein drugs extends to personalized medicine and targeted therapies, underscoring the versatility of these established drug modalities.

Monoclonal antibodies (mAbs), established drug modalities with hundreds of FDA-approved entities, have significantly advanced treatment in oncology, infectious diseases, and inflammatory conditions. Their targeted therapeutic approach uniquely allows them to differentiate between diseased and healthy cells, offering high specificity. This ability, combined with their complex mechanisms of action, positions mAbs as a superior choice in precision medicine over other modalities. Although mAbs face challenges like limited tissue penetration and potential immunogenicity, ongoing advancements in antibody engineering and technical innovations are progressively overcoming these obstacles, enhancing their efficacy and expanding their therapeutic applications. These developments highlight the substantial role of monoclonal antibodies in modern healthcare, solidifying their status as key therapies in various medical fields.

In modern medicine, drug modalities have evolved from traditional small molecules to cutting-edge modalities such as gene and cell therapies. In a series of articles, we will explore the diverse spectrum of drug modalities, ranging from mature and well-established modalities to emerging biotechnological breakthroughs poised to shape the future of therapeutic interventions and personalized medicine. In this first article, we focus on small molecule drug modalities and overview their properties, advantages, and limitations, as well as their current and future impact in medicine.