1. Introduction: Targeted Therapies Gaining Momentum

The biopharmaceutical sector in 2024-2025 has seen rapid advancements in oligonucleotides (oligos) and antibody-drug conjugates (ADCs), transforming treatments for complex diseases.

In 2024, the US FDA approved 50 new drugs; four were peptide/ oligonucleotide-based (TIDEs), including two oligo-TIDEs, highlighting their clinical significance.

The ADC field showed robust growth in 2024, with a 33% increase in new drug entities and a 23% rise in new clinical trials.

Progress is driven by better biological understanding, advanced engineering, manufacturing improvements, and AI in drug discovery.

2. Oligonucleotide Therapeutics: Maturing Precision

Imetelstat (Rytelo™) (Geron): Approved June 2024 for certain Myelodysplastic Syndromes (MDS) patients. A first-in-class telomerase inhibitor aptamer with a novel 3'-amino substitution for stability. Phase 3 showed significant transfusion independence.
Olezarsen (Tryngolza™) (Ionis): Approved December 2024 for Familial Chylomicronaemia Syndrome (FCS). An antisense oligonucleotide (ASO) targeting APOC-III mRNA, using the ESC-GalNAc liver-targeting platform. Phase 3 showed significant triglyceride and APOC-III reduction; offered as an at-home autoinjector.

Delivery: GalNAc conjugates (e.g., olezarsen) are key for liver targeting. Lipid nanoparticles (LNPs) remain vital for various RNA modalities. Efficient extra-hepatic delivery (e.g., to CNS, muscle) is a major ongoing challenge.
Chemistry: Novel chemical modifications (e.g., imetelstat's 3'-amino group, phosphorothioates, 2'-O-Methyl, LNAs, PMOs) enhance stability, binding, and reduce off-target effects.
Mechanisms: Diverse mechanisms include ASOs, siRNAs, aptamers, splicing modulators, and miRNA targeting.

Market Growth: Oligo therapy market projected from $5.55 billion (2024) to $9.82 billion by 2029. Oligo CDMO market to grow from $2.55 billion (2024) to $18.37 billion by 2034.
Manufacturing: Shift from solid-phase (SPOS) to more scalable liquid-phase oligonucleotide synthesis (LPOS).

Membrane-enabled one-pot LPOS shows high stepwise filtration yields (97–100%) and good crude purity (e.g., ~72% for an 18mer) using fewer phosphoramidite equivalents than SPOS.
Purification via ultrafiltration/ diafiltration (UF/DF) faces challenges with charged impurities.
Trend towards stable liquid API formulations to avoid lyophilisation bottlenecks.
Process Analytical Technology (PAT) and continuous manufacturing are gaining traction.
Recent innovation (July 2024): Template-independent enzymatic RNA synthesis (Wyss Institute/ EnPlusOne).

Regulatory: FDA issued final guidance on "Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics" in June 2024, covering immunogenicity, delivery, and DDIs.

An antisense therapy for hereditary angioedema is anticipated for FDA approval.

Ionis: Phase 3 data for olezarsen in severe hypertriglyceridaemia (sHTG) expected Q3 2025; zilganeursen data for Alexander disease also expected later in 2025.
Alnylam: FDA approval for vutrisiran in ATTR amyloidosis with cardiomyopathy expected
Arrowhead: Plozasiran PDUFA date for FCS is November 18, 2025. Initial data for ARO-INHBE expected by end of 2025.

Datopotamab Deruxtecan (Dato-DXd; Datroway™) (AstraZeneca/ Daiichi Sankyo): FDA approved January 2025 for HR-positive, HER2-negative breast cancer. TROPION-Breast01 showed median PFS of 6.9 months vs 4.9 months for chemotherapy.
Enhertu® (Trastuzumab Deruxtecan) (AstraZeneca/ Daiichi Sankyo): Label expansion FDA approved January 2025 for HR-positive, HER2-low/ultralow metastatic breast cancer (DESTINY-Breast06: mPFS 13.2 vs 8.1 months). DESTINY-Breast11 (early-stage HER2+) showed improved pCR.
Disitamab Vedotin (RC48) (Seagen/ RemeGen): RCTS trial (1st line GC/GEJC, +tislelizumab+S-1, updated May 2025): cORR 89.4%, mPFS 12.7 months.
Sacituzumab Tirumotecan: Approved in China, showing global ADC market expansion.

Linker-Payload Optimisation: Focus on cleavable linkers (for bystander effect) and non-cleavable linkers (for stability). Hydrophilic linkers improve solubility.
Payloads: Expanding beyond tubulin inhibitors (MMAE, DM1) to potent topoisomerase I inhibitors (deruxtecan, SN-38) and emerging classes like RNA polymerase II inhibitors. Higher DARs (e.g., ~8) being explored.
Antibody Engineering: Bispecific ADCs (e.g., ZW49, BL-B01D1) for enhanced specificity.
Site-Specific Conjugation: Increasingly used for homogenous ADCs with defined DAR, improving PK and therapeutic window (e.g., Synaffix's GlycoConnect).
Emerging Modalities: Dual-payload ADCs, Probody-drug conjugates, immunostimulatory ADCs, Degrader-Antibody Conjugates (DACs).

Market Growth: ADC market surpassed $10bn sales in 2023. Projections vary, e.g., $12.36bn (2024) to $29.9bn by 2034 (CAGR 9.23%). Another projects $7.75bn (2024) to $11.06bn by 2030 (CAGR 6.2%).
Deals: 99 ADC deals worth $64.3 billion in 2024, indicating strong industry confidence.
Manufacturing: Complex, often reliant on CDMOs. Samsung Biologics announced a new dedicated ADC facility (Jan 2025). Focus on DAR control, potent compound handling, and linker stability. Most ADCs are lyophilised; stable liquid formulations are a key goal.

Radiance Biopharma & CSPC Megalith (Feb 2025): Deal for ROR-1 targeted ADC RB-164.
ALX Oncology: Plans IND submission for EGFR-targeted ADC ALX2004 in Q1 2025.

The oligo, ADC, and AOC fields remain exceptionally dynamic, with ongoing efforts to unlock new targets, improve delivery (especially extra-hepatic), enhance therapeutic indices, and overcome resistance.

Hybrid modalities like AOCs represent a significant convergence of "Antibody" and "TIDES" technologies.

Increasing focus on patient-centricity (e.g., at-home administration for oligos , reducing ADC toxicities ).

Collaborative forums like the Antibody & TIDES conference are vital for sharing insights and driving these fields forward.