List of Drug Discovery Modalities

Drug discovery modalities are classifications of therapeutic methods based on drug mechanisms of action, structure, and manufacturing technology. In recent years, modalities have diversified due to technological innovation, and the necessary testing and evaluation items to assess the efficacy and safety of each differ. This article provides a list of representative drug discovery modalities.

Modality

What are drug discovery modalities?Treatment/attack methods that indicate how to act against the cause of a diseaseThis refers to the following. For example, even when targeting HER2, which is involved in cell proliferation, in cancer treatment, the means of attack vary. Trastuzumab binds to HER2 and inhibits proliferation signals, while pertuzumab suppresses proliferation by preventing HER2 from binding to other receptors. In this way,Even if they target the same molecule (HER2), different drug modalities are used if their mechanisms of action and treatment methods differ.is classified as.

Why are modalities increasing?

Drug discovery modalities areEvolving and diversifying to solve new drug discovery challengesInitially, there were proteins that could not be targeted by low-molecular-weight drugs, so antibody drugs that could recognize specific targets with high precision emerged. However, antibodies are not effective against intracellular targets, so PROTACs that degrade target proteins were developed. Furthermore, nucleic acid drugs have been commercialized in response to the need to target RNA itself rather than proteins. New modalities are born to overcome challenges that cannot be addressed by existing technologies.

List of Modality Types

Modality	feature	Main non-clinical evaluation
Small molecule drug	Easily acts on intracellular targets and is easy to administer orally.	Pharmacokinetics, Pharmacodynamics, and Safety
Antibody drug	Acts on extracellular targets with high specificity	ADA・Pharmacology and Pharmacokinetics
Nucleic acid medicine	Control of RNA expression	Organizational distribution, pharmacokinetics, and safety
Peptide and mid-molecule drugs	Having intermediate characteristics between small molecules and antibodies	Stability, Pharmacokinetics, Efficacy, and Pharmacology
Cell and gene therapy	To use cells and genes themselves for treatment	Pharmacological effects, immunological evaluation, and safety
Regenerative medicine	To regenerate cells and tissues	Pathological model, drug efficacy and pharmacology, safety

Small molecule drug

Small molecule drugs are,Low molecular weight and easily acts on intracellular targetsis a characteristic modality. Many formulations are available for oral administration, and manufacturing costs can be kept relatively low, allowing them to be used for a wide range of diseases. On the other hand, they can easily act on targets other than the intended ones, and side effects and drug resistance can become issues.

Required non-clinical evaluation
For small molecule drugs, we evaluate whether the drug sufficiently reaches the target tissue (pharmacokinetics), binds to the target protein and exhibits the expected pharmacological effect (target engagement), and whether there are any safety issues. Typical studies include pharmacokinetic studies, intratumoral distribution analysis, target engagement evaluation, and safety pharmacology studies.

EGFR inhibitor

• AdaptationIt is primarily used for non-small cell lung cancer with EGFR gene mutations.
• Mechanism of actionIt inhibits EGFR tyrosine kinase activity and suppresses cell proliferation signals, thereby inhibiting the proliferation and survival of cancer cells.

BCR-ABL inhibitor

• AdaptationIt is used for chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia, among others.
• Mechanism of actionIt inhibits the tyrosine kinase activity of the BCR-ABL fusion protein and blocks the abnormal proliferation signals of leukemia cells.

BTK inhibitor

• AdaptationChronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia are among the target diseases.
• Mechanism of actionBTK (Bruton's Tyrosine Kinase) is inhibited to suppress B-cell receptor signaling, thereby suppressing the proliferation and survival of malignant B-cells.

Antibody drug

Antibody drugs areIt has high specificity for the target molecule, allowing it to act while suppressing its effects on normal cells.is a modality with this characteristic. It primarily acts on extracellular target molecules and is expected to have high therapeutic efficacy. On the other hand, challenges include the fact that it is mainly administered by injection, high manufacturing costs, and the need to consider immunogenicity.

Required non-clinical evaluation
In antibody therapeutics, we evaluate whether the drug reliably binds to the target molecule and exerts its pharmacological effect (Target Engagement), whether it is properly distributed and maintained in the body (pharmacokinetics), and whether there are any issues with immune responses or safety. Typical evaluations include Target Engagement assessment, ADA (anti-drug antibody) assessment, tissue distribution analysis, and safety studies.

Anti-PD-1 antibody

• AdaptationIt is used in various types of cancer, such as malignant melanoma, non-small cell lung cancer, and renal cell carcinoma.
• Mechanism of actionBy inhibiting the binding of PD-1 and PD-L1, T cell activity is restored, activating immune function to attack cancer cells.

Anti-HER2 antibody

• AdaptationHER2-positive breast cancer, HER2-positive gastric cancer, and other tumors that overexpress HER2 are targeted.
• Mechanism of actionIt specifically binds to the HER2 receptor, inhibiting proliferation signals and eliminating tumor cells through ADCC (antibody-dependent cellular cytotoxicity).

anti-VEGF antibody

• AdaptationIt is widely used for solid tumors such as colorectal cancer, non-small cell lung cancer, and ovarian cancer.
• Mechanism of actionIt binds to VEGF to inhibit angiogenesis, thereby suppressing tumor growth by limiting the supply of oxygen and nutrients to the tumor.

Nucleic acid medicine

Nucleic acid drugs areIt can regulate gene expression by targeting DNA and RNAThis modality is characterized by [...]. Because it can act on molecules that were difficult to target with conventional small-molecule drugs or antibody-based therapeutics, it is viewed as a promising new treatment option. On the other hand, since it is easily degraded in the body, the development of technologies for efficient delivery to target tissues (DDS) is a critical challenge.

Required non-clinical evaluation
In nucleic acid drug development, evaluation focuses on whether the drug can be sufficiently delivered to target tissues or

siRNA

• AdaptationIt is used in treatments that suppress specific gene expression, such as hereditary diseases and liver diseases.
• Mechanism of actionRNA interference (RNAi) is used to degrade target mRNA and suppress the production of the causative protein.

Antisense oligonucleotide

• Adaptation: It is primarily used to treat hereditary diseases such as spinal muscular atrophy and Duchenne muscular dystrophy.
• Mechanism of actionIt binds complementarily to the target RNA and regulates gene expression through the degradation of RNA and control of splicing.

mRNA

• Adaptation: In addition to vaccines for infectious diseases, research is underway to apply this technology to cancer immunotherapy and treatments for rare diseases.
• Mechanism of actionIt exerts its therapeutic effect by introducing the target mRNA into cells and temporarily producing the proteins needed for treatment.

Peptide and mid-molecule drugs

Peptides and medium-molecular-weight drugs are,Possessing intermediate characteristics between small molecule drugs and antibody drugs, it can achieve both high target selectivity and excellent efficacy.This is about modality. It is easily effective on molecules that are difficult to target with small molecule drugs, and is attracting attention as a new drug discovery method. On the other hand, because they can be easily degraded in the body and sometimes oral administration is difficult, formulation design and delivery technology are required.

Required non-clinical evaluation
For peptides and medium-molecular-weight drugs, we evaluate whether they can maintain sufficient stability in the body (stability evaluation), whether they reach their target and exert their therapeutic effect (pharmacokinetics and pharmacodynamics), and whether there are any safety concerns.Typical evaluations include plasma stability studies, pharmacokinetic studies, pharmacodynamic studies, and safety studies.

GLP-1 receptor agonists

• Adaptation: It is used to treat type 2 diabetes and obesity, with the goal of managing blood sugar levels and promoting weight loss.
• Mechanism of action: It stimulates the GLP-1 receptor to promote insulin secretion and improves blood glucose levels and body weight by delaying gastric emptying and suppressing appetite.

Cyclic Peptide

• AdaptationDrug discovery is being advanced across a wide range of disease areas, including infectious diseases, cancer, and autoimmune diseases.
• Mechanism of actionThe cyclic structure provides high binding affinity and stability, selectively binding to target proteins to control biological functions.

Macrocycle Pharmaceuticals

• AdaptationApplications are also expected for diseases that have been difficult to target with conventional pharmaceuticals, such as cancer and infectious diseases.
• Mechanism of actionBy leveraging the large cyclic structure, a broad binding surface is formed, allowing interaction with target molecules that are difficult to bind with small molecule drugs, with high affinity.

Cell and gene therapy

Cell and gene therapy isAiming for a fundamental cure using the patient's own body, provided cells, or genes.It is a modality. It is expected to be applied to diseases that were difficult to treat with conventional drugs, and its practical application is progressing, especially in the fields of cancer and genetic diseases. On the other hand, the manufacturing process is complex, and quality control and long-term safety evaluation are important.

Required non-clinical evaluation
In cell and gene therapy, we evaluate whether therapeutic cells appropriately reach their targets and exert sufficient effects (pharmacodynamics), function safely in the body for extended periods, and whether there are no issues with safety or immune responses. Typical evaluations include pharmacodynamic studies, biodistribution analysis, immunological evaluations, and safety studies.

CAR T-cell

• AdaptationIt is used for blood cancers such as B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma.
• Mechanism of actionCARs (chimeric antigen receptors) are introduced into patient-derived T cells, enabling them to recognize and selectively attack and eliminate cancer cells expressing specific antigens on their surface.

CAR-NK

• AdaptationThis is a cell therapy primarily for blood cancers, with potential applications also expected for solid tumors.
• Mechanism of actionCAR-expressing NK cells recognize target antigens and kill cancer cells using their innate immune functions.

TCR-T

• AdaptationThese are being developed and are in practical use for cancers that target specific tumor antigens, such as sarcomas and malignant melanomas.
• Mechanism of actionT cells engineered with T cell receptors (TCRs) that recognize tumor antigens attack cancer cells by recognizing intracellular antigens.

Regenerative medicine

再生医療は、細胞や組織を利用して損傷した臓器や組織の機能回復を目指すモダリティです。従来の薬物療法では治療が難しかった疾患への新たな選択肢として期待されており、眼科や整形外科、循環器など幅広い分野で研究・実用化が進んでいます。一方で、細胞品質の管理や長期的な有効性・安全性の評価が重要です。

Required non-clinical evaluation
再生医療では、移植した細胞や組織が目的部位で生着・機能するか（薬効薬理）、適切に分化・増殖するか、安全性に問題がないかを評価します。代表的な評価には、病態モデルを用いた薬効薬理試験、生着・分化評価、腫瘍形成性評価、安全性試験などがあります。

iPS細胞

• Adaptation：加齢黄斑変性や脊髄損傷、パーキンソン病などを対象とした再生医療の研究・開発が進められています。
• Mechanism of action：人工多能性幹細胞（iPS細胞）から目的の細胞へ分化させて移植し、損傷した組織や臓器の機能回復を目指します。

ES細胞

• Adaptation：網膜疾患や神経疾患などを対象とした再生医療の研究や細胞治療への応用が進められています。
• Mechanism of action：胚性幹細胞（ES細胞）の高い分化能を活用し、必要な細胞へ分化誘導して移植することで組織の再生を図ります。

間葉系幹細胞（MSC）

• Adaptation：変形性関節症、脊髄損傷、急性移植片対宿主病（GVHD）などへの応用が期待されています。
• Mechanism of action：組織修復を促すサイトカインや増殖因子を分泌するとともに、免疫反応を調節することで組織の修復や炎症の改善に寄与します。

モダリティによってCRO選びは変わる

創薬モダリティとは、病気に対する治療アプローチを分類したものであり、近年は低分子医薬だけでなく、抗体医薬や核酸医薬、細胞・遺伝子治療、再生医療など多様なモダリティが実用化されています。それぞれで作用機序や体内での挙動が異なるため、必要となる非臨床評価や試験項目も異なります。適切な評価を行うには、各モダリティの特性を理解し、専門的な知見や評価技術を備えたCROを選定することが、医薬品開発を円滑に進める重要なポイントとなります。