# Cross-Modality Immunotherapy Target Report

**Generated:** April 2026 | **Source:** pirlygenes v2.1.0 | **Author:** auto-curated

This report ranks tumor-associated antigens by the breadth and maturity of
therapeutic modalities targeting them: ADCs, bispecific antibodies, T-cell
engagers (TCEs), CAR-T, TCR-T cell therapy, and radioligand therapy (RLT).
Targets pursued across multiple modalities represent higher-confidence
therapeutic antigens with validated biology.

---

## Tier 1 -- Approved in 3+ modalities

These targets have the strongest clinical validation, with approved therapies
in at least three independent modalities.

| Target | Modalities | ADC | Bispecific/TCE | Cell Therapy | RLT |
|--------|------------|-----|----------------|--------------|-----|
| **CD19** | 3 | Zynlonta (approved) | Blinatumomab (approved) | Kymriah, Yescarta, Tecartus, Breyanzi (CAR-T approved) | -- |
| **EGFR** | 3 | Akalux (approved, Japan) | Amivantamab (approved) | -- | -- |
| **ERBB2/HER2** | 4 | Enhertu, Kadcyla, Aidixi (approved) | Zenocutuzumab (approved) | Phase I TCEs | Clinical trials (RLT) |
| **DLL3** | 4 | Phase 3 ADC (rova-T) | Tarlatamab (approved) | Phase II TCEs | ABD-147 Ac-225 (clinical) |

**Recommendation:** CD19 and EGFR are the most validated multi-modality
targets. HER2/ERBB2 has the deepest pipeline across all four platforms.
DLL3 is the only target with active programs in all four modalities,
making it uniquely important for SCLC/neuroendocrine tumors.

---

## Tier 2 -- Approved in 2 modalities

| Target | Modalities | Status summary |
|--------|------------|----------------|
| **BCMA/TNFRSF17** | ADC + CAR-T + Bispecific | Blenrep (ADC, re-approved 2025), Abecma/Carvykti (CAR-T), Teclistamab/Elranatamab/Linvoseltamab (bispecific) |
| **FOLH1/PSMA** | RLT + ADC + TCE | Pluvicto (RLT, approved), PSMA-ADC (Phase 3), REGN-4336 (TCE Phase 2) |
| **MS4A1/CD20** | Bispecific + RLT | Mosunetuzumab/Epcoritamab/Glofitamab (approved), Zevalin (RLT, historical) |
| **ERBB3/HER3** | ADC + Bispecific | Patritumab deruxtecan (Phase 3), Zenocutuzumab (approved for NRG1+) |
| **CD33** | ADC + TCE | Mylotarg (approved, re-approved 2017), ANJ-564 (TCE Phase I) |
| **MAGEA4** | TCR-T + TCE | Tecelra (approved, first TCR-T), IMA-401 (TCER Phase I) |

**Recommendation:** BCMA is the most targetable myeloma antigen with three
approved modality classes. PSMA is the model for theranostic RLT and is
expanding to ADC/TCE. MAGEA4 is the first validated CTA target with an
approved cellular therapy.

---

## Tier 3 -- Multi-modality Phase 3 (convergent, no approval yet)

| Target | Modalities | Lead programs |
|--------|------------|---------------|
| **CD276/B7-H3** | ADC + TCE | Risvutatug rezetecan (GSK, Phase 3 SCLC), Ifinatamab deruxtecan (Phase 3 SCLC), TAK-280 (TCE Phase 2) |
| **CLDN18.2** | ADC + TCE | AZD0901 (Phase 3 gastric), IBI343 (Phase 3 gastric), AZD-5863 (TCE Phase 2) |
| **ROR1** | ADC + TCE | Zilovertamab vedotin (Phase 3 DLBCL), GNC-035 (TCE Phase 2) |
| **TACSTD2/TROP2** | ADC + RLT | Trodelvy/Datroway (approved), Sacituzumab tirumotecan (5 Phase 3 trials), RLT clinical |
| **FOLR1** | ADC + RLT | Elahere (approved), Rinatabart sesutecan (2 Phase 3 trials), RLT discontinued (kidney toxicity) |

**Recommendation:** B7-H3/CD276 and CLDN18.2 are the most active Phase 3
targets in solid tumors, each with multiple competing ADCs and TCEs.
TROP2 has the most diverse pipeline with 5+ Phase 3 ADC trials across
breast and lung.

---

## Tier 4 -- Emerging multi-modality targets (Phase 1-2)

| Target | Modalities | Key programs |
|--------|------------|-------------|
| **VTCN1/B7-H4** | ADC + TCE | AZD8205 (Phase 2), GEN-1047 (TCE Phase 2) |
| **GPC3** | TCE + RLT | CM-350 (TCE Phase 2), RYZ-801 (RLT Phase 1, BMS) |
| **MSLN** | ADC + TCE | Anetumab ravtansine (Phase 2), JNJ-79032421 (TCE Phase 1) |
| **STEAP1** | TCE + RLT | Xaluritamig (TCE Phase 1), RLT clinical (prostate) |
| **CEACAM5** | ADC + TCE | Tusamitamab ravtansine (discontinued), BA-1202 (TCE Phase 1) |
| **ENPP3** | ADC + TCE | AGS-16C3F (Phase 2), JNJ-87890387 (TCE Phase 1) |

---

## pMHC / CTA targets -- expression-dependent therapies

These targets are recognized as peptide-MHC complexes rather than surface
proteins, requiring HLA matching but offering access to intracellular
antigens inaccessible to conventional antibodies.

| Target | Best therapy | Phase | Format | Developer |
|--------|-------------|-------|--------|-----------|
| **MAGEA4** | Tecelra (afami-cel) | **Approved** (FDA 2024) | TCR-T cell therapy | Adaptimmune |
| **PRAME** | IMA203 | **Phase 3** (SUPRAME) | TCR-T cell therapy | Immatics |
| **PRAME** | Brenetafusp (IMC-F106C) | **Phase 3** | ImmTAC (pMHC TCE) | Immunocore |
| **PRAME** | IMC-P115C | Phase 1 | HLE-ImmTAC | Immunocore |
| **PMEL/gp100** | Tebentafusp | **Approved** (FDA 2022) | ImmTAC (pMHC TCE) | Immunocore |
| **PIWIL1** | IMC-R117C | Phase 1/2 | ImmTAC (pMHC TCE) | Immunocore |
| **MAGEA4/A8** | IMA-401 | Phase 1 | TCER (pMHC TCE) | Immatics |
| **TP53 R175H** | CLSP-1025 | Phase 1 | Bispecific scDb-Fc | Clasp Therapeutics |

**Recommendation:** PRAME is the most active CTA target with two independent
Phase 3 programs (TCR-T and ImmTAC). PIWIL1 is a novel CTA target entering
clinical development for GI cancers. TP53 R175H is the first neoantigen-
targeting TCE, opening a new category for mutation-specific pMHC therapies.

---

## Methodology

Targets were scored by: (1) number of distinct modalities with active programs,
and (2) sum of development-step scores per modality (Approved=5, Phase 3=3,
Phase 2=2, Phase 1=1, Preclinical=0.5). Data sourced from pirlygenes curated
datasets covering ADC-approved, ADC-trials, bispecific-antibodies-approved,
multispecific-tcell-engager-trials, CAR-T-approved, TCR-T-approved, and
radioligand-targets. All NCT numbers verified against ClinicalTrials.gov.

## Key references

- D'Angelo SP et al. Lancet 2024;403:1460-1471 (Tecelra/MAGEA4 TCR-T approval)
- Gong J et al. Lancet Oncol 2025;26(2) (AZD0901/CLDN18.2 ADC)
- Shen L et al. Nature Medicine 2025;31(9):3028-3036 (IBI343/CLDN18.2 ADC)
- Xu B et al. Nature Medicine 2025 (Sacituzumab tirumotecan/TROP2)
- Cheng Y et al. Cancer Cell 2026 (Risvutatug rezetecan/B7-H3)
- Lee HJ et al. NEJM Evidence 2022;1(1) (Zilovertamab vedotin/ROR1)
- Wang Y et al. Front Cell Dev Biol 2021;9:656993 (PIWIL1 as CTA target)
