Bispecific Antibodies in DLBCL & Myeloma: Clinical Insights for Physicians

Introduction to Bispecific Antibodies in Oncology

Bispecific antibodies (BsAbs) are an innovative class of immunotherapies designed to target two distinct antigens or epitopes simultaneously. Unlike conventional monoclonal antibodies, BsAbs can redirect immune effector cells to tumor cells, block multiple oncogenic pathways, or combine immune checkpoint inhibition with tumor-directed therapy.

In hematologic malignancies such as diffuse large B-cell lymphoma (DLBCL) and multiple myeloma, T-cell engaging BsAbs, known as BiTEs, have shown significant anti-tumor activity. They work by bridging cytotoxic T cells to tumor-specific antigens, enabling targeted cell killing while amplifying the immune response.

Beyond blood cancers, emerging BsAb platforms are being explored in solid tumors, focusing on pathways such as angiogenesis, metastasis, and immune regulation. These antibodies also allow combination strategies with antibody-drug conjugates (ADCs), checkpoint inhibitors, or standard chemotherapy to enhance efficacy and potentially overcome resistance.

With several BsAbs already approved and numerous candidates in clinical trials, understanding their mechanisms, clinical applications, and safety profiles is essential for physicians aiming to incorporate these therapies into modern oncology practice.

Understanding BiTEs: Mechanism of Action in DLBCL and Myeloma

Bispecific T-cell engagers (BiTEs) represent a specialized subclass of bispecific antibodies designed to harness the cytotoxic potential of T lymphocytes against malignant cells. Their mechanism centers on a simple yet powerful concept: bringing T cells into close proximity with tumor cells to facilitate immune-mediated killing.

A BiTE is engineered with two binding domains - one targets CD3 on T cells, and the other binds a tumor-associated antigen such as CD19 or BCMA, which are commonly expressed in diffuse large B-cell lymphoma (DLBCL) and multiple myeloma, respectively. By simultaneously engaging both cell types, BiTEs form an immunologic synapse, activating T cells independent of major histocompatibility complex (MHC) presentation. This activation triggers T-cell proliferation, cytokine release, and direct cytotoxic activity against the tumor cell.

What distinguishes BiTEs from conventional therapies is their ability to continuously redirect T cells toward malignant targets, even at low effector-to-target ratios. In clinical studies, BiTEs have shown rapid onset of anti-tumor responses, making them valuable for heavily pretreated or relapsed patients.

However, T-cell overactivation can lead to adverse effects such as cytokine release syndrome (CRS) or neurotoxicity, requiring careful monitoring. Despite these challenges, BiTEs are redefining treatment paradigms in hematologic oncology with growing clinical evidence supporting their use.

BsAb Platforms: Current and Emerging Technologies

Bispecific antibody (BsAb) platforms have expanded rapidly, offering diverse technological solutions to optimize efficacy, safety, and manufacturability. Early BsAbs faced challenges such as structural instability, short half-life, and complex production. Today, multiple engineering strategies have addressed these issues, resulting in a wide array of clinically viable platforms.

One major approach is fragment-based designs, such as the BiTE format, which links two single-chain variable fragments (scFvs). While highly potent, these molecules are small and require continuous infusion due to short half-lives. To overcome this limitation, Fc-containing formats such as IgG-like BsAbs have been developed, improving stability, half-life, and effector functions like antibody-dependent cellular cytotoxicity (ADCC).

Emerging technologies include “knobs-into-holes” engineering to promote correct heavy-chain pairing, dual-variable domain antibodies (DVD-Igs) that stack two variable regions, and CrossMab designs that swap domains to ensure correct light- and heavy-chain assembly. These platforms enable more precise targeting, reduced mispairing, and scalable production.

Novel BsAb formats are also exploring multi-specific approaches, where a single molecule targets three or more epitopes, expanding therapeutic potential. As these technologies evolve, they are being applied across hematologic cancers and solid tumors, setting the stage for next-generation immuno-oncology therapeutics with improved clinical outcomes.

Angiogenesis Modulation by Bispecific Antibodies

Angiogenesis, the process of new blood vessel formation, is critical for tumor growth, survival, and metastasis. Traditional anti-angiogenic therapies, such as VEGF inhibitors, have shown clinical benefit but are often limited by resistance and incomplete suppression of tumor vasculature. Bispecific antibodies (BsAbs) offer a novel strategy to more effectively target angiogenesis while simultaneously engaging the immune system.

BsAbs can be engineered to block vascular endothelial growth factor (VEGF) pathways while engaging immune effector mechanisms. For example, dual-targeting antibodies may simultaneously inhibit VEGF signaling and activate T cells, enhancing both anti-angiogenic and immunologic tumor control. This dual action disrupts the tumor blood supply, improves immune cell infiltration, and reduces the immunosuppressive microenvironment created by abnormal vasculature.

In preclinical and early clinical studies, BsAbs that target angiogenesis alongside tumor-associated antigens or immune checkpoints have demonstrated promising efficacy. These agents may overcome limitations of single-target therapies by preventing tumor escape mechanisms, such as upregulation of alternative pro-angiogenic factors.

By integrating vascular targeting with immune modulation, BsAbs represent a powerful therapeutic option for malignancies where angiogenesis plays a central role. Their clinical development could lead to more durable responses in both hematologic and solid tumors.

Targeting Metastasis with Bispecific Immunotherapies

Metastasis remains the leading cause of cancer-related mortality, driven by tumor cell dissemination, immune evasion, and establishment of secondary growth sites. Conventional therapies often fail to fully eradicate metastatic disease due to tumor heterogeneity and resistance mechanisms. Bispecific immunotherapies provide a novel approach by directly linking immune effector cells to metastatic tumor targets, enhancing the precision and potency of anti-tumor activity.

Bispecific antibodies (BsAbs) can simultaneously bind a tumor-associated antigen on metastatic cells and an activating receptor on T cells or NK cells, such as CD3 or CD16. This dual engagement facilitates targeted killing of disseminated tumor cells, even at distant sites, while bypassing MHC restrictions. In addition, BsAbs can be designed to block pathways crucial for metastatic spread, such as adhesion molecules or growth factor receptors, while simultaneously recruiting immune surveillance.

Preclinical studies suggest that BsAbs may improve immune infiltration into metastatic niches, disrupting the immunosuppressive microenvironment and reducing tumor escape. Combination strategies pairing BsAbs with checkpoint inhibitors or antibody-drug conjugates (ADCs) may further enhance efficacy against metastatic disease.

By uniting direct tumor targeting with immune activation, bispecific immunotherapies hold significant promise for controlling metastasis and improving long-term survival in oncology patients.

Immune Regulation and T-Cell Engagement Strategies

The ability to harness and regulate T-cell activity is central to the therapeutic success of bispecific antibodies (BsAbs). These agents are uniquely engineered to redirect T cells toward tumor cells, bypassing the need for antigen presentation through the major histocompatibility complex (MHC). By binding CD3 on T cells and tumor-associated antigens such as CD19, BCMA, or CD20, BsAbs create an artificial immunologic synapse that activates T-cell cytotoxicity.

Once engaged, T cells release perforin and granzymes, leading to tumor cell lysis, while also secreting cytokines that amplify the immune response. Importantly, BsAbs can recruit even resting or naïve T cells, broadening the immune arsenal available against malignant cells. However, this powerful mechanism requires careful regulation, as uncontrolled T-cell activation can result in cytokine release syndrome (CRS) and neurotoxicity.

Innovative strategies are being explored to fine-tune T-cell engagement, including step-up dosing regimens, split dosing, and the use of modified BsAb constructs with reduced CD3 affinity to mitigate toxicity. Combination approaches with checkpoint inhibitors may also sustain T-cell activity by preventing exhaustion.

Through these regulatory and engagement strategies, BsAbs offer a potent means to balance efficacy with safety, enabling durable anti-tumor responses in both hematologic malignancies and solid tumors.

Combination Approaches: BiTEs Plus ADCs

The integration of bispecific T-cell engagers (BiTEs) with antibody-drug conjugates (ADCs) represents a promising strategy to enhance therapeutic efficacy in oncology. While BiTEs redirect T cells to malignant cells for immune-mediated killing, ADCs deliver cytotoxic payloads directly into tumor cells via tumor-specific antibodies. Together, these modalities provide complementary mechanisms that may overcome resistance and broaden clinical benefit.

In this approach, ADCs can debulk tumors by inducing direct apoptosis, reducing tumor burden and immunosuppressive signaling. This creates a more favorable environment for BiTEs to activate T cells and sustain immune pressure against residual disease. Conversely, BiTE-mediated immune activation may eradicate tumor cells that escape ADC targeting, addressing heterogeneity within the tumor population.

Preclinical evidence suggests synergy between the two platforms, with ADCs enhancing antigen presentation and immune visibility, while BiTEs drive long-term immune surveillance. Early-phase clinical studies are beginning to explore these combinations in hematologic malignancies such as diffuse large B-cell lymphoma (DLBCL) and multiple myeloma, where single-agent activity has shown limitations.

The BiTE–ADC combination holds the potential to provide deeper, more durable responses by uniting direct cytotoxicity with immune engagement, positioning it as a frontier strategy in next-generation cancer therapy.

Clinical Evidence Supporting BiTE + ADC Combinations

Emerging clinical evidence highlights the potential synergy between bispecific T-cell engagers (BiTEs) and antibody-drug conjugates (ADCs) in hematologic malignancies and select solid tumors. Early-phase trials have demonstrated that combining these modalities may improve depth and durability of responses compared to either approach alone.

In diffuse large B-cell lymphoma (DLBCL), ADCs such as polatuzumab vedotin have shown strong activity in relapsed or refractory disease. When paired with CD3-engaging bispecific antibodies targeting CD19 or CD20, preliminary studies report enhanced tumor clearance and improved progression-free survival. The ADC reduces tumor bulk and antigen shedding, while the BiTE sustains immune-mediated killing of residual cells, even those with heterogeneous antigen expression.

In multiple myeloma, BCMA-targeted ADCs like belantamab mafodotin combined with BCMA-directed BiTEs have been explored to address relapsed/refractory patients. Early data suggest improved response rates, with some patients achieving minimal residual disease negativity. Importantly, careful dose scheduling has been key to balancing toxicity, particularly ocular events from ADCs and cytokine release syndrome (CRS) from BiTEs.

Though larger randomized studies are needed, current evidence indicates that BiTE + ADC combinations may deliver complementary cytotoxic and immunologic benefits, offering physicians a powerful treatment paradigm for difficult-to-treat cancers.

BNT327: BioNTech’s Bispecific Antibody Profile

BNT327 is an innovative bispecific antibody that merges two complementary and validated mechanisms into a single molecule targeting both PD-L1 and VEGF-A. This dual targeting aims to reinvigorate T-cell–mediated anti-tumor immunity by inhibiting PD-L1 while simultaneously disrupting tumor angiogenesis via VEGF-A neutralization. Notably, this bispecific format is designed to localize anti-VEGF activity within the tumor microenvironment, which may enhance precision and reduce systemic exposure. By normalizing tumor vasculature, BNT327 could improve drug delivery and synergize with combination therapies.

BioNTech has advanced BNT327 into more than 20 ongoing or planned clinical trials, with over 1,000 patients treated to date. It is currently being evaluated in global Phase III, registrational-potential trials for first-line extensive-stage small cell lung cancer (ES-SCLC), non-small cell lung cancer (NSCLC), and has a planned Phase III study in triple-negative breast cancer (TNBC) slated for late 2025.

In early 2025, BioNTech completed the acquisition of Biotheus to secure full global rights to BNT327 and expand its oncology pipeline and manufacturing capacity. Further strengthening its clinical development, BioNTech entered into a co-development and co-commercialization partnership with Bristol Myers Squibb, valued at up to $11 billion, underscoring the therapeutic and commercial potential of BNT327.

BMS Bispecifics: Pipeline and Therapeutic Potential

Bristol Myers Squibb (BMS) is strategically advancing its bispecific antibody pipeline with a focus on high-value oncology assets while reprioritizing certain programs. The company is leveraging both internal development and external partnerships to expand its presence in the bispecific immuno-oncology space.

BNT327 (in collaboration with BioNTech):
BMS has partnered with BioNTech on BNT327, a dual-targeting bispecific antibody directed against PD-L1 and VEGF-A. This agent is designed to simultaneously block immune checkpoint signaling and tumor angiogenesis. It is currently in global Phase III trials for extensive-stage small cell lung cancer (ES-SCLC) and non-small cell lung cancer (NSCLC), with a trial in triple-negative breast cancer (TNBC) anticipated to begin by late 2025.

BL-B01D1 (EGFR x HER3 bispecific ADC):
BMS is also developing BL-B01D1 through a collaboration with SystImmune. This bispecific antibody–drug conjugate targets EGFR and HER3 and is linked to a topoisomerase inhibitor payload. It is being evaluated in a Phase I global trial for metastatic or unresectable NSCLC and has shown encouraging early anti-tumor activity across solid tumors.

Program Withdrawals and Refocusing:
BMS recently halted development of alnuctamab, a BCMA-targeting bispecific for multiple myeloma, despite progression toward Phase III. The decision underscores the company’s strategy of prioritizing assets with the strongest clinical and commercial potential.

Safety and Adverse Event Considerations

While bispecific antibodies (BsAbs) have demonstrated remarkable clinical activity, their potent immune-engaging mechanisms are associated with distinct safety challenges. The most common and clinically significant adverse event is cytokine release syndrome (CRS), driven by rapid T-cell activation and cytokine secretion upon engagement with tumor cells. CRS typically manifests as fever, hypotension, and elevated inflammatory markers, requiring close monitoring and step-up dosing strategies to mitigate risk.

Neurotoxicity, also known as immune effector cell–associated neurotoxicity syndrome (ICANS), is another key concern. Symptoms range from mild confusion and headache to seizures and cerebral edema in severe cases. The pathophysiology is not fully understood but is thought to involve endothelial activation, cytokine-driven inflammation, and disruption of the blood–brain barrier.

Hematologic toxicities, including cytopenias, and infection risk due to immunosuppression, are also relevant, particularly in heavily pretreated patients with lymphoma or myeloma. Organ-specific toxicities may vary depending on the targeted antigens and antibody design.

To address these risks, clinical protocols often employ stepwise dosing, premedication with corticosteroids or anti-IL-6 therapies, and hospitalization during early cycles. Ongoing research aims to optimize BsAb design and administration to preserve efficacy while reducing the incidence and severity of treatment-related toxicities.

Biomarkers and Patient Selection for BsAb Therapy

The clinical success of bispecific antibodies (BsAbs) relies heavily on identifying patients most likely to benefit while minimizing toxicity. Biomarkers play a central role in refining patient selection strategies. Antigen expression on tumor cells is the primary determinant; for example, CD19, CD20, and BCMA expression levels guide eligibility in B-cell malignancies. Standardized assays to quantify target density are increasingly important for predicting therapeutic response and avoiding off-target toxicity.

Beyond antigen expression, immune contexture is a key biomarker domain. Baseline T-cell count, functionality, and exhaustion markers (e.g., PD-1, TIM-3, LAG-3) influence clinical outcomes, as BsAbs require robust T-cell engagement. Tumor microenvironment (TME) features, including immune suppressive cells like regulatory T cells and myeloid-derived suppressor cells, may also shape treatment efficacy.

Circulating biomarkers such as cytokine profiles and soluble antigen fragments are being studied to predict risk of cytokine release syndrome (CRS) and to guide dosing strategies. Emerging genomic and transcriptomic signatures may help stratify patients by likelihood of response or toxicity.

Ultimately, an integrated biomarker-driven approach encompassing antigen density, immune fitness, and TME composition will optimize patient selection, improve outcomes, and reduce unnecessary exposure to BsAb therapy in non-responders.

Comparative Review: Bispecific Antibodies vs CAR-T

Bispecific antibodies (BsAbs) and chimeric antigen receptor T-cell (CAR-T) therapies represent two transformative approaches in cancer immunotherapy, each with unique advantages and limitations. BsAbs are engineered proteins that simultaneously bind tumor-associated antigens and T-cell receptors, redirecting T cells to kill malignant cells. Their off-the-shelf availability provides a logistical advantage, enabling rapid treatment initiation without the delays inherent to cell collection, genetic modification, and expansion required for CAR-T therapies.

CAR-T therapies, in contrast, are living drugs with the potential for long-term persistence and durable remission, particularly in hematologic malignancies like B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. However, CAR-T manufacturing is complex, costly, and often inaccessible to patients with rapidly progressing disease.

Safety profiles also differ. Both modalities carry risks of cytokine release syndrome (CRS) and neurotoxicity, though the incidence and severity are generally higher with CAR-T. BsAbs, being titratable and reversible, offer greater flexibility in toxicity management. Nevertheless, BsAbs may require continuous or repeated dosing, while CAR-T cells can expand and persist for extended disease control.

Overall, BsAbs provide broader accessibility and flexible use, whereas CAR-T offers potential curative outcomes in select patients, making these modalities complementary rather than competitive.

Future Directions in Bispecific Immuno-Oncology

The future of bispecific antibodies (BsAbs) in immuno-oncology is poised to expand significantly, driven by advances in protein engineering, biomarker discovery, and combinatorial strategies. Next-generation BsAbs are being designed with improved pharmacokinetics, longer half-lives, and enhanced tumor selectivity to reduce off-target toxicity. Innovations such as trispecific antibodies and conditional activation formats are under investigation, aiming to further refine immune redirection and improve therapeutic windows.

A key direction is the integration of BsAbs with other immunotherapies, such as checkpoint inhibitors, CAR-T cells, or cancer vaccines, to overcome resistance mechanisms and enhance antitumor efficacy. Additionally, combining BsAbs with targeted small molecules or antibody-drug conjugates may create synergistic effects by simultaneously modulating immune activity and tumor signaling pathways.

Personalized medicine will play a central role in optimizing BsAb therapy. Advances in biomarker-driven patient selection, such as identifying tumor antigen density, immune microenvironment features, and genomic signatures, will help match patients to the most effective bispecific strategies.

As clinical experience grows, BsAbs are expected to move beyond hematologic malignancies into solid tumors, where challenges like tumor penetration and immunosuppressive environments are being addressed. Collectively, these innovations point toward a future where BsAbs become foundational pillars of cancer immunotherapy.

Practical Considerations for Physicians in Clinical Practice

Integrating bispecific antibodies (BsAbs) into routine oncology practice requires physicians to carefully balance clinical efficacy, safety, and patient-centered care. A key consideration is the complexity of administration, as many BsAbs are given via continuous infusion or frequent intravenous dosing, which may require specialized infusion centers and additional patient monitoring. Physicians must also remain vigilant for immune-related toxicities, including cytokine release syndrome (CRS) and neurotoxicity, which often necessitate proactive management protocols, early intervention strategies, and coordination with critical care teams.

Patient selection remains essential, with careful evaluation of tumor antigen expression, prior therapies, comorbidities, and performance status guiding treatment decisions. Physicians must also account for logistical factors such as hospitalization requirements for early dosing, supportive medications, and monitoring schedules, which may affect both patient quality of life and healthcare resource utilization.

Another practical aspect is education - patients and caregivers should be counseled thoroughly about potential side effects, signs of toxicity, and when to seek urgent care. Physicians also need to navigate evolving reimbursement and access challenges as these therapies enter clinical practice. Ultimately, successful integration of BsAbs depends on multidisciplinary collaboration, structured toxicity management pathways, and individualized treatment planning to ensure both safety and therapeutic benefit.

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