CD38/CD3 Bispecific Antibody for Selective Myeloma Cell Killing

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Solution Overview

Problem

Current treatments for multiple myeloma, such as monoclonal antibodies like Daratumumab, face resistance mechanisms and have poor overall survival rates for patients with relapsed disease, necessitating novel therapeutic strategies.

Innovation Solution

Development of a new anti-CD38/CD3 Bispecific T cell-engager antibody, Bi38-3, which triggers T-cell mediated lysis of CD38-positive MM cells, avoiding resistance to anti-CD38 mAbs and preserving B cells from T cell cytotoxic activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If anti-CD38 monoclonal antibodies like Daratumumab are used to treat multiple myeloma, then initial therapeutic effect is achieved, but resistance mechanisms develop leading to poor overall survival in relapsed patients

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidoverall survival

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent divides the therapeutic approach into two distinct functional domains: one targeting CD38 on myeloma cells for antigen recognition, and another targeting CD3 on T cells for immune activation. This segmentation allows the antibody to engage different immune mechanisms (ADCC/CDC through Fc region and direct T cell activation through CD3 binding) rather than relying on a single mechanism that can be resisted.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The bispecific antibody performs multiple functions simultaneously: it binds CD38 on myeloma cells, binds CD3 on T cells, recruits T cells to kill myeloma cells, and can still mediate ADCC and CDC through its Fc region. This multi-functionality ensures that even if one mechanism is resisted, other mechanisms remain effective, addressing the relapse problem.

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Productivity

If T cell cytotoxic activity is enhanced to kill MM cells, then tumor burden is reduced, but risk of off-target cytotoxicity to normal B cells increases

Engineering Contradiction:

Improvetumor cell killing efficiencyVSAvoidoff-target cytotoxicity

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The antibody structure is designed with distinct binding specificities: the CD38-binding domain specifically recognizes myeloma cells (which overexpress CD38), while the CD3-binding domain specifically recruits T cells. This localized specificity ensures T cell cytotoxicity is directed only at CD38-positive myeloma cells, sparing normal B cells and other healthy tissues that do not express CD38.

Inventive Principle:

Principle #3Local quality

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

Bi38-3 mediates efficient and selective T cell killing of MM cells, reducing tumor burden by six-fold in three days, demonstrating potential as a frontline or relapse treatment.

Implementation Method 1

a) a first domain, said first domain comprising a first amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:3, said first domain being capable of specifically binding to an extracellular domain of CD38

Methodology Applied

Scientific EffectAntibody-antigen binding:

Implementation Method 2

The antibody of the present invention can be used for the treatment of a hematological malignancy by inducing antibody dependent cellular cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC)

Methodology Applied

Scientific EffectADCC:

Implementation Method 3

Methodology Applied

Scientific EffectComplement-dependent cytotoxicity:

Data Source

PatentUS20250388692A1Antibodies having specificity for CD38 and uses thereof

Publication Date: 2025.12.25 INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM)

AI summary

CD38 is also expressed in a variety of malignant hematological diseases, including multiple myeloma. In the present invention, the inventors have generated a new antibody against CD38 that could be suitable for producing bispecific antibodies as well as CAR-T cells. In particular, the inventors report the development of Bi38-3, a new bispecific T cell engager that targeted CD38 on MM cells and recruited cytotoxic T cells through the CD3ε. Bi38-3 lacked the Fc region of natural mAb, which contributes to resistance processes, but triggered T cells to proliferate, release cytokine and lyse CD38 positive MM cells in vitro. Similarly, Bi38-3 induced autologous T cells to eliminate tumor plasma cells isolated from MM patients both at diagnosis and at relapse. The cytotoxicity triggered by Bi38-3 was restricted to cells expressing high levels of CD38 and preserved the integrity of T, B and NK lymphocytes in vitro. Importantly, Bi38-3 rapidly reduced tumor cells in an MM1.S xenograft mouse model of human MM. Taken together, the results show that the antibody of the present invention is an effective reagent to specifically eliminate CD38 positive malignant cells without significantly affecting CD38 lowly expressing cells and represents a promising novel immunotherapeutic tool for the treatment of malignant hematological diseases, and especially multiple myeloma.