Antibody Immunotherapy in Oncology

Introduction

Monoclonal antibody (mAb)–based therapies have reshaped systemic cancer treatment by selectively targeting tumor or immune regulatory proteins. Modern platforms extend beyond conventional IgG molecules to include antibody–drug conjugates (ADCs), bispecific T‑cell engagers (BiTEs), Fc‑engineered variants, radioimmunoconjugates, and checkpoint inhibitors. Understanding mechanisms, biomarkers, toxicity patterns, and resistance pathways is essential for optimized, individualized application.

Core Mechanisms of Action

| Mechanism | Description | Representative Agents |
|———–|————-|———————–|
| Antigen blockade | Inhibits ligand–receptor signaling that drives proliferation/survival | Trastuzumab (HER2), Cetuximab (EGFR) |
| ADCC (antibody‑dependent cellular cytotoxicity) | FcγRIIIa (CD16) engagement recruits NK cells/macrophages to lyse opsonized cells | Rituximab (CD20), Daratumumab (CD38) |
| CDC (complement‑dependent cytotoxicity) | C1q binding → membrane attack complex formation | Ofatumumab (CD20) |
| Direct apoptosis / agonism | Receptor clustering or death receptor activation | Obinutuzumab (Type II anti‑CD20) |
| Immune checkpoint blockade | Releases T‑cell inhibition | Nivolumab (PD‑1), Ipilimumab (CTLA‑4) |
| Payload delivery (ADCs) | Internalization → cytotoxic payload release | Ado‑trastuzumab emtansine, Enfortumab vedotin |
| T‑cell redirection (bispecific) | Simultaneous tumor antigen + CD3 binding activates polyclonal T cells | Blinatumomab (CD19×CD3), Teclistamab (BCMA×CD3) |
| Radiosensitization / targeted radiation | Delivers radionuclide to malignant cells | Ibritumomab tiuxetan (90Y‑Zevalin) |
| Innate immune modulation | Engages/activates macrophages, DCs | Tafasitamab (enhanced Fc), Magrolimab (CD47 blockade) |

Major Antibody Classes

1. Conventional (“Naked”) Monoclonal Antibodies

Humanized or fully human IgG1/IgG4 formats; rely on signaling blockade plus Fc‑mediated effector functions.

2. Antibody–Drug Conjugates (ADCs)

• Components: targeting mAb + linker (cleavable vs non‑cleavable) + payload (microtubule inhibitor, DNA damaging agent, topoisomerase I inhibitor).
• Key determinants: antigen density/internalization rate, bystander effect potential (membrane‑permeable payload), drug–antibody ratio (DAR), linker stability.

3. Bispecific Antibodies / T‑Cell Engagers

• Formats: tandem scFv (BiTE), IgG‑like asymmetric antibodies, 2:1 high‑affinity constructs.
• Mechanism: forms immunologic synapse between CD3+ T cells and antigen‑positive tumor cells independent of native MHC/peptide presentation.
• Distinct toxicities: cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS).

4. Immune Checkpoint Inhibitors (ICIs)

• Targets: CTLA‑4, PD‑1, PD‑L1 (approved); emerging: LAG‑3 (relatlimab), TIGIT, TIM‑3, B7‑H3, CD73, adenosine A2A, CD47.
• Combination rationale: vertical (PD‑1 + CTLA‑4), metabolic axis (adenosine + PD‑1), or innate priming (CD47 + macrophage activation).

5. Fc Engineering and Glyco‑Optimization

• Afucosylation enhances FcγRIIIa binding → increased ADCC (e.g., obinutuzumab, mogamulizumab).
• pH‑dependent antigen binding for improved recycling (“sweeper” antibodies).

6. Radioimmunoconjugates & Immunocytokines

• Targeted radiation (90Y, 131I) or fused cytokines (e.g., IL‑2, IL‑12) to enrich local immune activation while moderating systemic exposure.

Biomarkers and Patient Selection

| Modality | Biomarker Examples | Notes |
|———-|——————-|——-|
| HER2 mAbs/ADCs | IHC 3+ / FISH amplification; HER2‑low (IHC 1+/2+, FISH–) now targetable by some ADCs | Heterogeneity matters for ADC response |
| CD20 mAbs | Uniform B‑cell antigen expression | Loss/modulation → resistance |
| ICIs | PD‑L1 TPS/CPS, TMB, MSI‑H/dMMR, POLE mutations, gene expression signatures | Composite biomarker strategies emerging |
| Bispecific (BCMA, CD19, GPRC5D) | Antigen density thresholds | Monitor for antigen escape |
| ADCs | Antigen expression, SLCO/ABC transporter status, DNA repair competency (for PBD/payload types) | Emerging predictive markers |

Resistance Mechanisms

• Antigen loss/downregulation or splice variants (CD19, BCMA).
• Fc effector attenuation (upregulated inhibitory FcγR, NK cell exhaustion).
• Upstream/downstream pathway reactivation (HER2 signaling bypass, EGFR mutations under anti‑EGFR pressure).
• Immune exclusion / suppressive TME (high myeloid-derived suppressor cells, TGF‑β, adenosine).
• Drug efflux / lysosomal sequestration (ADCs).

Key Toxicities and Monitoring

| Class | Common Toxicities | Mitigation |
|——-|——————-|————|
| ICIs | Immune‑related adverse events (irAEs): dermatitis, colitis, hepatitis, endocrinopathies, pneumonitis | Grade‑based steroids; hormone replacement; taper; hold/rechallenge algorithms |
| ADCs | Cytopenias, neuropathy, ocular toxicity, ILD/pneumonitis (e.g., trastuzumab deruxtecan), hepatotoxicity | Baseline pulmonary eval; early imaging for cough/dyspnea; dose holds/reductions |
| Bispecifics | CRS, ICANS, cytopenias, infections (hypogammaglobulinemia) | Step‑up dosing, premedication (steroids/antihistamines), tocilizumab for CRS |
| Anti‑CD38 / anti‑CD20 | Infusion reactions, cytopenias, HBV reactivation (CD20), hypogammaglobulinemia | Premedication; antiviral prophylaxis (HBV); vaccination planning |
| HER2 mAbs/ADCs | Cardiotoxicity (trastuzumab), diarrhea (neratinib combo), ILD (deruxtecan) | Baseline & periodic LVEF; early ILD detection |
| EGFR mAbs | Acneiform rash, hypomagnesemia, diarrhea | Prophylactic skin regimen; Mg replacement |

Practical Clinical Workflow (Example: Initiating a Bispecific)

1. Baseline: CBC, CMP, viral hepatitis/HIV, quantitative immunoglobulins, disease imaging, performance status.
2. Step‑up dosing schedule to mitigate CRS; inpatient monitoring for initial doses if high tumor burden.
3. Premedication: acetaminophen, antihistamine ± corticosteroid.
4. CRS management: Grade 1—supportive; ≥Grade 2—tocilizumab ± steroids; distinguish from sepsis.
5. Infection prophylaxis: antiviral (HSV/VZV), PJP prophylaxis as indicated, IVIG for recurrent severe infections.
6. Response assessment: disease‑specific criteria (e.g., Lugano, IMWG) at defined intervals; track MRD where validated.

Combination Strategies

• ICI + ADC: Potential synergy via immunogenic cell death but monitor overlapping pneumonitis risk.
• Bispecific + checkpoint blockade: Experimental approach to overcome T‑cell exhaustion induced post‑engagement.
• Targeted therapy + mAb (e.g., BRAF/MEK + anti‑PD‑1 in melanoma): Sequence to minimize toxicity and preserve efficacy.

Emerging Directions

• Conditioned (tumor‑activated) antibodies with protease‑cleavable masks to limit systemic immune activation.
• Multi‑specific (tri‑specific) constructs targeting tumor antigen + costimulatory receptor + CD3.
• Fc domain tuning for selective engagement of activating vs inhibitory Fcγ receptors.
• Antibody–RNA or antibody–nanoparticle hybrids delivering genetic payloads (siRNA, mRNA) to malignant cells.

Key Takeaways

• Antibody immunotherapies exert effects through direct signaling blockade, immune effector recruitment, checkpoint modulation, or payload delivery.
• Precision deployment requires integrating antigen expression, immune biomarkers, and patient comorbidities.
• Early recognition and grade‑appropriate management of toxicities preserve treatment continuity and outcomes.
• Engineering innovations (bispecificity, conditional activation, optimized Fc, next‑gen ADCs) continue to expand therapeutic windows and indications.