Bispecific & multispecific antibodies

01Overview and value chain#

Markers EC: Directive 2001/83/EC + FDA bispecific antibody guidance | OECD: Bio-pharma | Regulator: FDA (USA), EMA (European Union), NMPA (China)

Bispecific and multispecific antibodies are engineered molecules that bind two or more antigens on a single IgG-like scaffold, reaching biology no monospecific antibody can. The dominant class is the T-cell engager: one arm binds CD3 on a T cell and the other a tumour antigen (CD20, BCMA, GPRC5D), forcing an immunological synapse and T-cell killing. Roche’s Lunsumio (mosunetuzumab, CD20xCD3) had its combination with Polivy accepted for FDA supplemental review in relapsed large B-cell lymphoma; Janssen reported Talvey (talquetamab, GPRC5DxCD3) plus Darzalex Faspro data in earlier-line myeloma; Regeneron’s linvoseltamab (BCMAxCD3) BLA was accepted for FDA review; AbbVie’s TEPKINLY (epcoritamab, CD20xCD3) was approved by the European Commission with lenalidomide and rituximab for follicular lymphoma; Genmab (DuoBody platform, epcoritamab co-originator) reported high response rates in elderly DLBCL; and BeiGene released first clinical data on its innovative bispecific.

The key directions of bispecific and multispecific antibodies are:

1. T-cell engagers (T-cell Engager): a CD3 arm recruits polyclonal T cells to a tumour antigen — Roche (Lunsumio, Columvi, CD20xCD3), Janssen (Tecvayli BCMA, Talvey GPRC5D), AbbVie/Genmab (TEPKINLY/epcoritamab CD20xCD3), Regeneron (linvoseltamab BCMA).
2. Dual-antigen co-binding (Dual Targeting): two non-CD3 arms co-target two disease pathways on one molecule, e.g. Roche’s Hemlibra (FIXa/FX) for hemophilia A, and emerging dual-oncology and dual-immunology designs.
3. Bispecific platforms (Bispecific Platform): the proprietary engineering that makes a stable two-arm molecule — Genmab DuoBody, Roche CrossMab/Knob-in-Hole, Regeneron Veloci-Bi, AbbVie/Duomab.
4. Multispecific and format innovation (Multispecific): tri-specifics and novel scaffolds (BiTE, DART) that extend the concept beyond two arms.

Sectoral value chain#

[two antigens / CD3 + tumour] ──> [format design + DuoBody/CrossMab engineering] ──> [stable bispecific drug]
                                              │
                                     (CHO manufacture + CDMO)
                                              │
                                              ▼
[approved off-the-shelf drug] <─── [clinical trial + BLA/MAA] <─────┘

Value chain levels#

Cross-cutting technologies of the sector:

• T-cell engager mechanism (T-cell Engager): the CD3 arm turns every endogenous T cell into a tumour killer, an off-the-shelf alternative to autologous CAR-T that competes for the same CD20 and BCMA targets.
• Bispecific platforms (Bispecific Platform): Genmab DuoBody, Roche CrossMab/Knob-in-Hole and Regeneron Veloci-Bi control correct heavy/light-chain pairing so a single cell makes one stable bispecific product.
• Oncology target selection (Oncology Targets): CD20 (lymphoma), BCMA and GPRC5D (myeloma), DLL3 (small-cell lung) anchor the approved and late-stage pipeline.

02US#

The US holds the densest approved-bispecific franchise — Janssen, Regeneron and AbbVie are US-based or US-listed, with the FDA approving the most bispecific products globally.

Janssen, Regeneron, AbbVie, FDA#

• Janssen: reported Talvey (talquetamab-tgvs, GPRC5DxCD3) plus Darzalex Faspro combination data demonstrating the strength of a bispecific combination in earlier-line relapsed/refractory multiple myeloma, complementing Tecvayli (teclistamab, BCMAxCD3).
• Regeneron: linvoseltamab (BCMAxCD3) BLA accepted for FDA review for relapsed/refractory multiple myeloma, extending Regeneron’s bispecific franchise alongside odronextamab (CD20xCD3).
• AbbVie: TEPKINLY (epcoritamab, CD20xCD3) in combination with lenalidomide and rituximab was approved by the European Commission for relapsed/refractory follicular lymphoma, broadening the CD20 T-cell-engager use.
• FDA framework: bispecifics are approved as biologics with class-level management of cytokine release syndrome and neurotoxicity, and step-up dosing to mitigate first-dose reactions.

03CN#

China’s bispecific field is the fastest-growing pipeline segment, with BeiGene among the leaders releasing first-in-class clinical bispecific data.

BeiGene, NMPA, pipeline growth#

• BeiGene: released first clinical data on its innovative bispecific antibody (双抗), extending a portfolio that has already made BeiGene a global oncology franchise; China runs one of the world’s largest bispecific pipelines.
• Domestic pipeline: numerous Chinese biotechs have CD3-based and dual-target bispecifics in the clinic under NMPA review, several reaching domestic approval.
• NMPA framework: the National Medical Products Administration approves bispecific antibodies under its biologics framework, aligning CMC and pharmacovigilance expectations with FDA and EMA.

04EU#

Europe contributes Roche’s bispecific franchise, Genmab’s DuoBody platform and the EMA’s centralised biologics authorisation.

Roche, Genmab, EMA#

• Roche (Switzerland): the FDA accepted a supplemental Biologics License Application for Lunsumio (mosunetuzumab, CD20xCD3) plus Polivy in relapsed/refractory large B-cell lymphoma; Roche also markets Columvi (glofitamab, CD20xCD3) and the dual-FIXa/FX Hemlibra for hemophilia A.
• Genmab (Denmark): its DuoBody platform underpins epcoritamab (co-developed with AbbVie), reporting high response rates in elderly diffuse large B-cell lymphoma, and a broader bispecific portfolio.
• EMA framework: bispecifics receive central EU marketing authorisation from the European Medicines Agency under Directive 2001/83/EC, with the PRIME pathway supporting early access for promising bispecifics.
• European CDMO: European CDMOs and CHO-based manufacturers participate in the biologics supply chain supporting bispecific CMC.

05Leading companies and research institutes#

06Tech stack and innovations#

The stack pairs dual-target format design with a stable bispecific engineering platform, CHO CMC manufacture, and structured clinical management of T-cell-engager toxicities.

1. T-cell engagers (T-cell Engager):
   • Roche’s Lunsumio (CD20xCD3) plus Polivy is under FDA supplemental review in large B-cell lymphoma, AbbVie/Genmab’s TEPKINLY (epcoritamab) is EC-approved in follicular lymphoma, and Janssen’s Tecvayli/Talvey and Regeneron’s linvoseltamab anchor the myeloma CD3-engager class.
   • The CD3 arm turns endogenous T cells into tumour killers, an off-the-shelf alternative to autologous CAR-T for the same targets.
2. Dual-antigen co-binding (Dual Targeting):
   • Roche’s Hemlibra (emicizumab, FIXa/FX) is the proof-of-concept that a dual-arm non-CD3 bispecific can transform a chronic disease (hemophilia A), and dual-oncology/dual-immunology designs extend the concept.
3. Bispecific platforms (Bispecific Platform):
   • Genmab’s DuoBody controls correct chain pairing so one cell secretes one stable bispecific; Roche’s CrossMab/Knob-in-Hole and Regeneron’s Veloci-Bi are the rival platforms.
4. Multispecific and format innovation (Multispecific):
   • Tri-specifics and fragment scaffolds (BiTE, DART) extend the concept beyond two arms, with BeiGene and others advancing next-generation multispecifics in the clinic.

07Value chains and production pipelines#

Industrial pipeline of a bispecific antibody drug (BLA / MAA, Directive 2001/83/EC)#

┌───────────────────────────┐      ┌───────────────────────────┐
│ 1. Target & format design │ ───> │ 2. Engineering &          │
└───────────────────────────┘      │    cell line              │
                                   └───────────────────────────┘
                                                   │
                                                   ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 4. Preclinical & clinical │ <─── │ 3. CMC manufacture        │
└───────────────────────────┘      └───────────────────────────┘
              │
              ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 5. Regulatory & approval  │ ───> │ 6. Launch & PV            │
└───────────────────────────┘      └───────────────────────────┘

Stage 1: Target and format design

Two (or more) antigens are selected — a CD3 T-cell arm plus a tumour antigen, or two disease-pathway targets — and the molecular format is chosen (full IgG-like, BiTE fragment, or DART).

Stage 2: Engineering and cell line

A proprietary platform (Genmab DuoBody, Roche CrossMab/Knob-in-Hole, Regeneron Veloci-Bi) enforces correct heavy/light-chain pairing, and a stable CHO production cell line is built and banked.

Stage 3: CMC manufacture

The bispecific is produced in CHO bioreactors (often via a CDMO), with upstream and downstream purification that separates the correctly-paired product from mis-paired by-products.

Stage 4: Preclinical and clinical

IND-enabling pharmacology, pharmacokinetics and toxicology support first-in-human trials, then pivotal trials (e.g. epcoritamab in follicular lymphoma, linvoseltamab in myeloma) generate the efficacy and safety dataset, with step-up dosing to manage first-dose CRS.

Stage 5: Regulatory and approval

A BLA (US) or MAA (EU) is filed; the FDA accepted Roche’s Lunsumio+Polivy sBLA and Regeneron’s linvoseltamab BLA, and the European Commission approved TEPKINLY plus lenalidomide/rituximab.

Stage 6: Launch and pharmacovigilance

Following approval, the bispecific launches with market access, patient-support and pharmacovigilance for CRS/ICANS and long-term safety, as the approved class (Lunsumio, Columvi, Tecvayli, Talvey, TEPKINLY, odronextamab) continues to expand.