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.